NON-HUMAN PRIMATE IMMUNE TOLERANCE COOPERATIVE STUDY GROUP

Release Date:  January 25, 2001

RFA:  RFA-AI-01-006 (This RFA has been reissued, see RFA-AI-06-018)

National Institute of Allergy and Infectious Diseases
 (http://www.niaid.nih.gov)
National Institute of Diabetes and Digestive and Kidney Diseases
 (http://www.niddk.nih.gov)

Letter of Intent Receipt Date:  June 11, 2001
Application Receipt Date:       July 17, 2001

PURPOSE

The Division of Allergy, Immunology, and Transplantation (DAIT) of the National 
Institute of Allergy and Infectious Diseases (NIAID) and the Division of 
Diabetes, Endocrinology, and Metabolic Diseases (DDEMD) of the National 
Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) invite 
applications from single institutions and consortia of institutions to 
participate in the Non-Human Primate Immune Tolerance Cooperative Study Group 
(NHPCSG).  The NHPCSG is a multi-center, cooperative research program focused on 
the study of immune tolerance in non-human primate models of kidney and islet 
allograft rejection, asthma and allergic diseases and autoimmune diseases.  The 
goals of this research program are to: evaluate the safety and efficacy of novel 
tolerance induction regimens; elucidate the mechanisms of the induction, 
maintenance and loss of tolerance; and develop and validate biomarkers for 
induction, maintenance, and loss of tolerance in these immune-mediated 
disorders.  For purposes of this Request for Applications (RFA), immune 
tolerance is defined as a lack of a pathogenic immune response to allogeneic, 
environmental, or self-antigens in the absence of ongoing immunosuppressive 
therapy.  Tolerance may be induced by a variety of approaches, including: clonal 
deletion, clonal anergy, immune deviation, or suppression.  Projects should be 
designed to meet these goals in established and new non-human primate models of 
kidney and islet transplantation, asthma and allergic diseases, and autoimmune 
diseases.  Because the ultimate purpose of this RFA is to develop candidate 
tolerogenic approaches for the treatment of immune-mediated diseases in humans, 
the sponsors expect that there will be reciprocal communication between the 
NHPCSG and the Immune Tolerance Network and Type 1 Diabetes TrialNet.

HEALTHY PEOPLE 2010

The Public Health Service (PHS) is committed to achieving the health promotion 
and disease prevention objectives of "Healthy People 2010," a PHS led national 
activity for setting priority areas.  This RFA, Non-Human Primate Immune 
Tolerance Cooperative Study Group, is related to Diabetes and Chronic Disabling 
Conditions.  Potential applicants may obtain a copy of "Healthy People 2010" at 
http://www.health.gov/healthypeople.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic for-profit and non-profit 
organizations, public and private institutions, such as universities, colleges, 
hospitals, laboratories, units of State and local governments, and eligible 
agencies of the Federal government.  Foreign institutions are not eligible to 
apply.  Racial/ethnic minority individuals, women, and persons with disabilities 
are encouraged to apply as Principal Investigators.

MECHANISM OF SUPPORT

The administrative and funding mechanisms to be used to undertake this program 
will be the Cooperative Agreement (U01) and the Multi-project Cooperative 
Agreement (U19), "assistance" mechanisms, rather than "acquisition" mechanisms.  
Under the cooperative agreement, the National Institutes of Health (NIH) purpose 
is to support and/or stimulate the recipient's activity by involvement in and 
otherwise working jointly with the award recipient in a partner role, but it is 
not to assume direction, prime responsibility, or a dominant role in the 
activity.  

Consistent with this concept, the dominant role and prime responsibility for the 
activity resides with the awardees for the project as a whole, although specific 
tasks and activities in carrying out the research will be shared among the 
awardees and the NIH Coordinators.

Essential elements of the multi-project cooperative agreement mechanism (U19) 
include: 

1.  A minimum of three interrelated individual research projects organized 
around a central theme;
2.  Collaborative efforts and interaction among independent projects and their 
investigators to achieve a common goal; 
3.  A single Principal Investigator who will be scientifically and 
administratively responsible for the group effort; 
4.  A single applicant institution that will be legally and financially 
responsible for the use and disposition of funds awarded; and 
5.  Where necessary, support for "Core" resources or facilities, each of which 
shall be utilized by at least two research projects in order to facilitate the 
research effort.  

Details of the responsibilities, relationships, and governance of a study funded 
under a cooperative agreement are discussed later in this document under the 
section "Terms and Conditions of Award."

The total project period for applications submitted in response to this RFA may 
not exceed five years.

FUNDS AVAILABLE

The estimated total funds (direct and facilities and administrative (F&A)) 
available for the first year of support for this RFA will be between $4,000,000 
and $6,000,000.  In fiscal year 2002, the NIH plans to make six to seven awards 
related to this RFA.  This level of support is dependent on (1) the receipt of a 
sufficient number of applications of high scientific merit, (2) the relative 
proportions of U01 and U19 applications, and (3) the availability of funds. 

Applications for U01 awards may not request budgets in excess of $500,000 total 
(direct and F&A) first-year costs.  Applications for U19 awards may not request 
budgets in excess of $1,000,000 total first-year costs.  The NIH Grants Policy 
governing grants administration and management will apply.  Although this 
program is provided for in the financial plans of the sponsoring institutes, 
awards pursuant to this RFA are contingent upon the availability of funds for 
this purpose.  Funding beyond the first and subsequent years of the grant will 
be contingent upon satisfactory progress during the preceding years and 
availability of funds.

RESEARCH OBJECTIVES

Background

The cosponsors of this RFA support research focused on immune tolerance, immune-
mediated diseases, diabetes, and kidney diseases, including the development of 
improved therapies to prevent these diseases and treat their complications.  
Supported research also focuses on the use of non-human primate models for 
studies that elucidate human health problems and disease processes.

The NIAID and NIDDK have made research on immune tolerance a high scientific 
priority and.  In the fall of 1997, NIAID initiated a scientific planning 
process designed to accelerate research in this area.  The broad-based, long-
range NIAID Plan for Research on Immune Tolerance is available at:
http://www.niaid.nih.gov/publications/immune/bookcover.htm 

The NIAID Expert Panel for Research on Immune Tolerance enthusiastically 
endorsed the conceptual framework, scope and timeliness of the plan and 
encouraged the NIAID to take a leadership role in designing and directing major 
research programs focused on immune tolerance, particularly with respect to the 
treatment of human disease.  Two subsequent expert panels, the NIAID Expert 
Panel on Ethical Issues in Clinical Trials of Transplant Tolerance and the 
Expert Review Panel for NIAID's Extramural Transplantation Research Program, 
identified non-human primate tolerance research as an essential step to provide 
"...critical data on safety, toxicity and potential efficacy that can not be 
obtained ethically in human clinical trials."  In 1998, NIAID established a 
program in non-human primate models of kidney and islet transplantation using 
the NIH Director’s 1% Transfer Authority Funds.  In 1999, this effort was 
expanded though an RFA, co-sponsored by NIAID, NIDDK, and the National Center 
for Research Resources (NCRR).  The current, RFA seeks to expand support for 
immune tolerance research in kidney and islet transplantation and initiate 
support for immune tolerance research in non-human primate models of other 
immune mediated diseases.

In September 1997, the Director of National Institutes of Health (NIH) and the 
Director of NIDDK sponsored - with the co-sponsorship of eight other Institutes 
and Centers of NIH - a unique landmark symposium on "Diabetes Mellitus: 
Challenges and Opportunities."  This symposium brought together over 150 
investigators to develop recommendations on how diabetes research should be 
intensified to close research gaps, take advantage of new technologies, and 
capitalize on highly promising research leads and advances.  One recommendation 
was the development of and access to larger animal models of diabetes.  
Subsequently the Congress established the Diabetes Research Working Group to 
develop a strategic research plan for NIH-funded diabetes research.  This plan, 
“Conquering Diabetes: A Strategic Plan for the 21st Century, Report Summary and 
Recommendations,” can be found at 
(http://www.niddk.nih.gov/federal/dwg/dwgsummary.htm).  This panel identified 
research on autoimmunity and the beta cell as one of five extraordinary 
opportunities and recommended expanded research on islet transplantation and 
immune intervention as well as support of centers using large animal models to 
test new therapies for type 1 diabetes.  

1.  Transplantation

Transplantation is now routine therapy for end-stage renal disease, with one-
year graft survival approaching 90% using standard immunosuppressive therapy.  
However, long-term graft survival has improved only slightly since the early 
1980s, with about 62% of cadaveric kidneys surviving five years post-transplant.  
For other organs (e.g., heart, liver, lung and pancreas), graft survival rates 
are similar.  While new immunosuppressive drugs have reduced acute rejection in 
the first year post-transplant, it is clear that these therapeutic improvements 
have only marginally altered long-term clinical outcomes.  

Therefore, current attention has focused on the potential for donor-specific 
immune tolerance to achieve long-term graft survival without non-specific, life-
long immunosuppressive therapies that have deleterious and often life-
threatening side effects.  Although certain promising tolerogenic regimens have 
been shown to induce donor-specific immune tolerance in animal models, and are 
being tested in humans for the treatment of selected autoimmune diseases, these 
approaches have not been rigorously evaluated in the transplant setting.  Both 
the Expert Panel on Immune Tolerance and the Expert Panel on Ethical Issues in 
Clinical Trials of Transplant Tolerance recommended that NIAID pursue tolerance 
research in non-human primate models of kidney and islet transplantation as a 
prelude to human clinical trials.  These recommendations were reinforced and 
expanded by the extraordinary opportunities as presented in the Congressionally-
requested report "Conquering Diabetes: A Strategic Plan for the 21st Century."

2.  Asthma and Allergic Diseases

Asthma and allergic diseases, including allergic rhinitis, atopic dermatitis, 
urticaria and anaphylaxis, are among the major causes of illness and disability 
in the United States.  NIAID vigorously pursues research on asthma and allergic 
diseases by fostering investigator-initiated projects and by supporting a 
national network of research centers, cooperative clinical studies, and 
demonstration and education research projects.  The cause, pathogenesis, 
diagnosis, treatment, and prevention of asthma and allergic diseases are major 
areas of emphasis for the NIAID Division of Allergy, Immunology, and 
Transplantation, and recent research advances have led to a better understanding 
of the pathogenesis of these diseases.  Nevertheless, translation of the basic 
research findings into new approaches to treatment and prevention of asthma and 
allergic diseases has been hampered by the lack of animal models that accurately 
simulate the important features of human disease.  This is particularly 
important with respect to asthma, for which there is increasing epidemiological 
and clinical evidence that early life changes in immune system function 
contribute to the development of the disease.  Because of the similarity in the 
development of the non-human primate immune system to that of man, there is a 
need for non-human primate models that will facilitate the investigation of the 
early life origins of asthma and the tracking of changes in immune function that 
occur as the disease progresses.  The Expert Panel convened to review the NIAID 
Extramural Asthma and Allergy research program underscored the limitations of 
currently available animal models of asthma and suggested that the NIAID support 
suitable non-human primate models.  This can be best accomplished through the 
coordinated, high quality infrastructure provided by expansion of the NHPCSG.

3.  Autoimmune Diseases

Autoimmune diseases, which are caused by immune reactions against self-antigens, 
affect more than five (5) percent of the U. S. population and disproportionately 
affect women.  These diseases are a significant cause of chronic morbidity, 
costing billions of dollars annually in health care expenses and lost 
productivity.  NIAID supports a program of basic and clinical research in 
autoimmunity.  NIDDK supports basic and clinical research on type 1 diabetes, 
inflammatory bowel disease and liver and kidney diseases resulting from 
autoimmune mechanisms.  Basic research focuses on: understanding the genetics of 
autoimmunity, elucidating the mechanisms that underlie self-tolerance, inducing 
self-tolerance, and characterizing the pathways of immune-mediated tissue 
destruction.  Knowledge gained from basic studies provides the rationale for: 
developing clinical tests to diagnose autoimmune diseases; therapies to prevent 
autoimmune diseases; and novel treatments for ongoing disease.  Efforts to 
induce tolerance in autoimmunity have focused primarily on the oral 
administration of antigens.  Oral tolerance can be induced in animal models and 
is now being evaluated in human diseases, including type 1 diabetes.  However, 
the encouraging responses in animal studies have not been duplicated in recent 
clinical trials of rheumatoid arthritis and multiple sclerosis.  There are a 
number of promising tolerogenic approaches other than oral tolerance that can be 
pursued, including: costimulatory blockade, anti-cytokine monoclonal antibodies, 
hematopoietic stem cell and bone marrow transplantation, and gene transfer-based 
therapies for cytokine modulation.  Expansion of the NHPCSG will follow the 
recommendation in The Report of the NIH Autoimmune Diseases Coordinating 
Committee and the Diabetes Research Working Group, which encourage the 
exploration of therapeutic approaches to autoimmunity in animal models that more 
faithfully mimic human autoimmune diseases.  In addition, the Expert Panel on 
Immune Tolerance and the Congressional-established Diabetes Research Working 
Group highlighted the need to evaluate the safety and efficacy of various 
tolerance induction regimens and agents in non-human primate models of 
autoimmune diseases.

4.  Non-Human Primates

Studies of existing and new tolerogenic treatment regimens in non-human primate 
models of kidney and islet transplantation, asthma and allergic diseases, and 
autoimmune diseases are critical to the design of scientifically sound and 
ethically acceptable clinical trials.  In addition, non-human primates are 
especially useful as they closely approximate the human immune system and 
physiology.  Non-human primates also allow collection of important biological 
samples necessary to validate new non-invasive or minimally invasive diagnostic 
tests for tolerance, graft function, survival, and rejection, asthma and 
allergic diseases, and autoimmune diseases.

Research Objectives and Scope

The purpose of this RFA is to support a multi-site cooperative research program 
to develop tolerance induction protocols in non-human primate models of immune-
mediated diseases.  For purposes of this RFA, immune tolerance is defined as a 
lack of a pathogenic immune response to allogeneic, environmental, or self-
antigens in the absence of ongoing immunosuppressive therapy.  Tolerance may be 
induced by a variety of approaches as described below.

All participating sites will use uniform controlled study designs and 
standardized data collection procedures.  Specifically, the cooperative research 
program will design and conduct:

1.  Studies on the safety and efficacy of tolerance induction therapies alone, 
in combination with immunosuppressive therapies, and in combination with 
immunosuppressive therapy withdrawal.  Approaches to immune tolerance may 
include, but are not limited to, the following:
o Co-stimulatory blockade
o Cytokine modulation
o Clonal deletion
o DNA vaccination
o Oral administration of antigen
o Bone marrow transplantation or donor-specific transfusion
o Other approaches such as leukocyte migration blockade, allergen- or 
autoantigen-specific immunotherapy, and the use of molecularly engineered cells 
and tissues for deletion or inactivation of pathogenic lymphocytes.
 
 2.  Studies of the underlying mechanisms of action of the therapeutic approaches 
being evaluated, including changes in immune response and function and measures 
of the induction, maintenance, and loss of donor-specific tolerance.  Possible 
approaches to mechanistic studies include, but are not limited to, the 
following:
o Quantitation of alloreactive, autoreactive, or allergen-specific T 
lymphocytes
o Analysis of alloreactive, autoreactive, or allergen-specific T cells for gene 
expression that correlates with functions such as inflammation or homing
o Comparison of samples from peripheral blood and urine with those from sites 
of rejection (for transplantation studies), autoimmune tissue destruction, or 
pulmonary function.

3.  Studies to develop, evaluate, and validate biomarkers of immune tolerance.  
This includes establishing appropriate measures (e.g., cytokines and/or their 
receptors, lymphocyte subsets, etc.), selecting appropriate samples (e.g., 
blood, urine, biopsies, etc.), and selecting appropriate techniques (e.g., 
quantitative PCR, DNA microarrays, imaging, cellular immune assays, etc.) for 
routine use.  Possible markers include: changes in gene or protein expression in 
blood, urine or biopsy materials; antibody or cytokine levels in blood, urine or 
biopsies; or in vitro and in vivo immune responsiveness to antigens as 
determined by T-cell proliferation, cytotoxic T-cell activity, antibody 
production, cytokine secretion, and immediate or delayed-type hypersensitivity.

This RFA will not provide support for:

o Studies in animal models other than non-human primates;
o Studies to improve the viability or supply of organs, tissues, or cells for 
transplantation;
o Preliminary development of immune-mediated disease models in non-human 
primates; or
o Xenotransplantation into non-human primates.

However, this RFA will provide support for costs associated with the procurement 
of allogeneic non-human primate islets and kidneys.

SPECIAL REQUIREMENTS

A.  Study Organization

1.  Steering Committee

A Steering Committee, composed of principal investigators, additional 
investigators where appropriate, and NIH staff will serve as the main governing 
body of the NHPCSG.  Specific details on the composition of the Steering 
Committee, its responsibilities, and the establishment of subcommittees are 
listed under “Terms and Conditions of Award, Collaborative Responsibilities.”

A broad range of scientific and technical expertise is required to carry out the 
objectives of this RFA, including extensive experience in: immune-mediated 
diseases; asthma and allergic diseases; autoimmune diseases; transplantation 
immunobiology and genetics; solid organ, cell, and tissue transplantation; non-
human primate models of immune system disorders; molecular and cellular biology, 
particularly as applied to the identification and evaluation of biomarkers and 
assay development and validation; research design and statistics; and veterinary 
care for non-human primates.  Each participating member of the Cooperative Study 
Group must possess scientific expertise in the appropriate areas under the 
direction of a senior scientist as the Principal Investigator responsible for 
the scientific, technical and administrative coordination and management of the 
awardee institution(s).

NIH will facilitate collaboration and coordination between the Cooperative Study 
Group and the Immune Tolerance Network (www.immunetolerance.org).  Close 
coordination among these two research programs will facilitate the development 
of safety, toxicity, and potential efficacy data from non-human primate models 
critical to the design and implementation of scientifically sound and ethically 
acceptable human trials for both existing and new tolerogenic approaches.  Close 
coordination will also enable the application of findings from non-human 
primates to the clinical setting with respect to important biomarkers and 
reliable assays to measure tolerance. 

2.  Data Coordination and Management

Each Cooperative Study Group member institution will be responsible for 
collecting, managing, interpreting, and assuring the quality of data collected 
on site.  Applicants should request support for all data collection and 
analyses, including a Statistical Coordinator, in their budgets.  For 
collaborative studies and specific data analyses, the Steering Committee will 
select a Statistical Coordinator from among the member institutions.  Applicants 
wishing to serve as a Data Coordinating Center for collaborative studies should 
request appropriate levels of support in their budgets.  The results of those 
analyses will be delivered to the Steering Committee which will determine: if 
and what further analyses should be performed; how the results are interpreted; 
whether the results impact ongoing data collection, ongoing studies, or future 
studies; and how the findings should be disseminated.  The awardees will retain 
custody of and have primary rights to all data developed under these awards, 
subject to Government rights of access consistent with HHS, PHS, and NIH 
policies.

B. Terms and Conditions of Award

The following terms and conditions will be incorporated into the Notice of Grant 
Award and provided to the Principal Investigator as well as the institutional 
official at the time of award.  These special terms and conditions pertaining to 
the scope and nature of the interaction between the NIH and the investigators 
are in addition to, and not in lieu of, otherwise applicable OMB administrative 
guidelines, HHS Grant Administration Regulations at 45 CFR part 74 and 92, and 
other HHS, PHS, and NIH Grant Administration policy statements.  Cooperative 
agreements are subject to the administrative requirements outlined in OMB 
circulars A-102 and A-110.  All pertinent HHS, PHS, and NIH grant regulations, 
policies and procedures, with particular emphasis on PHS regulations at 42 CFR 
Part 52 and HHS regulations at 45 CFR Part 74, are applicable.

The administrative and funding mechanisms to be used to undertake this program 
will be the Cooperative Agreement (U01) and the Multi-project Cooperative 
Agreement (U19), "assistance" mechanisms, rather than "acquisition" mechanisms.  
Under the cooperative agreement, the National Institutes of Health (NIH) purpose 
is to support and/or stimulate the recipient's activity by involvement in and 
otherwise working jointly with the award recipient in a partner role, but it is 
not to assume direction, prime responsibility, or a dominant role in the 
activity.  

Consistent with this concept, the dominant role and prime responsibility for the 
activity resides with the awardees for the project as a whole, although specific 
tasks and activities in carrying out the research will be shared among the 
awardees and the NIH Coordinators

1.  Awardee Rights and Responsibilities

Awardees will have primary responsibility for defining the research objectives, 
approaches, and details of the projects within the guidelines of the RFA and for 
performing the scientific activities. Specifically, awardees have primary 
responsibility as described below.

Steering Committee Membership and Meeting Attendance

Each Principal Investigator and additional investigators where appropriate from 
a consortium, will serve as a voting member of the Steering Committee and will 
participate in all scientific decisions.  Each Steering Committee member will be 
responsible for attending all Steering Committee meetings and participating in 
all other Steering Committee activities, e.g., conference calls, special 
subcommittee meetings as may be necessary, etc.  Applicants are instructed to 
request funds for travel to Steering Committee meetings in their budgets.

Protocol Development and Conduct

All Cooperative Study Group institutions, upon acceptance of an award, agree to 
participate in all studies, including those that involve collaborations with 
biotechnology and pharmaceutical companies, as specified by the Steering 
Committee.  For all studies implemented by the Cooperative Study Group, the 
Steering Committee will (1) define the objectives and approaches of treatment 
protocols, mechanistic studies, and tolerance assay and biomarker development; 
(2) design the consensus protocols and procedures for study conduct and 
monitoring; and (3) determine the procedures for data collection and quality 
control.  Furthermore, the Steering Committee will decide which treatment 
protocols will be conducted at multiple centers and which will be conducted at 
individual institutions.  Cooperative Study Group institutions will be required 
to accept and implement the studies and data collection procedures approved by 
the Steering Committee.  Studies will proceed into the implementation stage only 
with the concurrence of the Steering Committee.  

Publication and Presentation of Study Findings

Early publication of major findings is encouraged.  Publications and oral 
presentations of work performed under this agreement will require appropriate 
acknowledgment of both the Cooperative Study Group and NIH support.  Analyses to 
be performed using the collective data from the Cooperative Study Group 
institutions will be determined and directed by the Steering Committee.  
Cooperative Study Group institutions wishing to perform analyses of local data 
will inform the Steering Committee of any such analyses prior to initiation in 
order to avoid duplication.  Review and approval by the Steering Committee, or a 
Publications Subcommittee, will be required for all analyses prior to 
publication or presentation according to criteria that will be developed by the 
Steering Committee.  

Monitoring Study Progress

The Steering Committee will establish mechanisms for assessing the performance 
of the Cooperative Study Group institutions.  This includes: quality, accuracy 
and timeliness of data collection and management; conscientious observance of 
study requirements; and presentation of study results at joint meetings with the 
Executive Committee of the Immune Tolerance Network.

Federally Mandated Regulatory Requirements

The PHS Policy on Humane Care and Use of Laboratory Animals requires that 
applicant organizations proposing to use vertebrate animals file a written 
Animal Welfare Assurance with the Office of Laboratory Animal Welfare, 
establishing appropriate policies and procedures for the humane care and use of 
live vertebrate animals in research activities supported by the PHS.  The PHS 
policy stipulates that an applicant organization, whether domestic or foreign, 
bears responsibility for the humane care and use of animals in PHS-supported 
research activities.

All institutions are required to comply, as applicable, with the Animal Welfare 
Act as amended (7 USC 2131 et sec.) and other Federal statutes and regulations 
relating to animals. These documents are available from the Office of Laboratory 
Animal Welfare, National Institutes of Health, Bethesda, MD 20892, (301) 496-
7163, http://grants.nih.gov/grants/olaw/olaw.htm

2.  NIH Staff Responsibilities

The NIH Coordinators will be the Immunobiology Section Chief, Transplantation 
Immunobiology Branch, DAIT, NIAID and the Senior Advisor for Diabetes, DDEMD, 
NIDDK.  The NIH Coordinators will have substantial scientific/programmatic 
involvement during the conduct of this activity through technical assistance, 
advice, and coordination above and beyond normal program stewardship for grants, 
as described below.

Steering Committee Membership and Meeting Attendance

The NIH Coordinators will serve as voting members of the Steering Committee, 
will attend all Steering Committee meetings, and will participate in other 
Committee activities, e.g., conference calls, special subcommittees, etc.
 
Protocol Development

As members of the Steering Committee, the NIH Coordinators will serve as a 
resource with respect to the design of treatment protocols and adjunct studies 
and will assist the Steering Committee in study development.

Study Materials

The NIH Coordinators, in coordination with the DAIT Office of Clinical 
Applications, will be responsible for coordinating the acquisition and 
distribution of study materials to be used in the treatment protocol developed 
by the consensus of the Steering Committee.

The NIH is not responsible for obtaining or distributing solid organs, tissues 
or cells to be used by the Cooperative Study Group.

Monitoring Study Performance

The NIH Coordinators will provide assistance to the Steering Committee in the 
development of mechanisms and procedures for monitoring study performance.  This 
includes: the accuracy, quality, and timeliness of data collection and 
management; consistency in observing study requirements; and presentation of 
study results at joint meetings with the Executive Committee of the Immune 
Tolerance Network.

The Government, via the NIH Coordinators, will have access to data generated 
under this Multi-Project Cooperative Agreement and may periodically review the 
data and progress reports.  NIH Staff may use information obtained from the data 
for the preparation of internal reports on the activities of the study.  
However, awardees will retain custody of and have primary rights to all data 
developed under these awards.

Publication and Presentation of Study Findings

The NIH Coordinators and other NIH representatives may contribute, through 
review, comment, analysis, and/or co-authorship, to reporting results of the 
studies conducted by the Cooperative Study Group to the research community and 
interested lay organizations.  Co-authorship by the NIH staff will be subject to 
approval in accordance with NIH policies regarding staff authorship of 
publications resulting from extramural awards. 

Organizational Changes

Certain organizational changes require the prior written approval of the NIH 
Coordinators.  These changes include the addition or replacement of a scientific 
investigator, affiliate, component, or research base that is associated with 
this research program.  A change in the Principal Investigator, or in any key 
personnel identified on the Notice of Award, must have the prior written 
approval of the appropriate NIH Grants Management Specialist in consultation 
with the NIH Coordinators and representatives of other sponsoring institutes.

Program Review

The NIH Coordinators will review the progress of the Cooperative Study Group 
through consideration of annual progress reports, periodic reports on ongoing 
progress, findings and future plans presented during meetings and conference 
calls, publications, site visits, etc. This review may include, but is not 
limited to, compliance with the study protocols, adherence to uniform data 
collection procedures, and participation in Steering Committee and other 
subcommittee meetings as necessary.

The NIH reserves the right to terminate or curtail the study (or any individual 
award) in the event of (a) a major breech of any Cooperative Study Group 
approved protocol, (b) substantive changes in the agreed-upon protocols to which 
the NIH does not agree, (c) reaching a major study endpoint substantially ahead 
of schedule with persuasive statistical significance, and (d) failure to meet 
the collaborative responsibilities as determined by the Steering Committee.

3.  Collaborative Responsibilities

A Steering Committee will serve as the main governing body of the NHPCSG.  At a 
minimum, the Steering Committee will be composed of the NIH Coordinators and the 
Principal Investigators of each award.  If the awardee is a consortium of 
institutions, one additional investigator from the consortium will serve on the 
Steering Committee, on an annual rotating basis, as determined by the protocols 
under development or implemented.  The Steering Committee will meet twice during 
the first 12 months of the project and annually thereafter.  The Steering 
Committee will select a Chairperson from among the non-Federal members during 
the first meeting of the Committee, to be convened by the NIH Coordinators.  

The Steering Committee will be responsible for all major scientific decisions 
and will have primary responsibility for developing the common treatment 
protocols, approving the design and implementation of all collaborative studies, 
facilitating the conduct and monitoring of all studies, analyzing and 
interpreting collaborative study data, and reporting collaborative study 
results.  Studies will proceed to the implementation stage only with the 
concurrence of the Steering Committee.  The responsibilities of the Steering 
Committee members are listed above under “Terms and Conditions of Award.”

Cooperative Study Group institutions will be required to accept and implement 
the studies and data collection procedures approved by the Steering Committee.  
Studies will proceed into the implementation stage only with the concurrence of 
the Steering Committee.

Subcommittees of the Steering Committee may be established as necessary to 
provide guidance to the Steering Committee on: assays for tolerance and 
biomarkers, data collection and analysis, collaboration with investigators 
outside of the Cooperative Study Group, and reporting and publication of 
collaborative studies.

4.  Arbitration

Any disagreement that may arise on scientific or programmatic matters (within 
the scope of the award) between award recipients and the NIH may be brought to 
arbitration.  An arbitration panel will be composed of three members - one 
selected by the Steering Committee (with the NIH members not voting) or by the 
individual awardee in the event of an individual disagreement, a second member 
selected by the NIH, and the third member with expertise in the relevant area 
and selected by the two prior members.  The Arbitration Panel will review any 
scientific or programmatic issue that is significantly restricting progress.  
While the decisions of the Arbitration Panel are binding, these special 
arbitration procedures will in no way affect the awardee's right to appeal an 
adverse action in accordance with PHS regulations at 42 CFR Part 50, subpart D, 
and HHS regulations at 45 CFR Part 16.

LETTER OF INTENT

Prospective applicants are asked to submit, by June 11, 2001, a letter of intent 
that includes a descriptive title of the overall proposed research; the name, 
address and telephone number of the Principal Investigator and all 
collaborators; and the number and title of this RFA.  Although the letter of 
intent is not required, is not binding, does not commit the sender to submit an 
application, and does not enter into the review of subsequent applications, the 
information that it contains allows NIH staff to estimate the potential review 
workload and to plan the review.  The letter of intent is to be sent to Dr. 
Priti Mehrotra at the address listed under “INQUIRIES.”

APPLICATION PROCEDURES

Applicants are strongly encouraged to call NIH program staff with any questions 
regarding the responsiveness of their proposed project to the goals of this RFA.

The research grant application form PHS 398 (rev. 4/98) is to be used in 
applying for these grants. Application kits are available at most institutional 
offices of sponsored research and from the Division of Extramural Outreach and 
Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 
7910, Bethesda, MD 20892-7910, telephone (301) 435-0714, email: 
GrantsInfo@nih.gov. Applications are also available on the World Wide Web at 
http://grants.nih.gov/grants/forms.htm.

Applications must be received by July 17, 2001.
 
For purposes of identification and processing, item 2a on the face page of the 
application must be marked "YES" and the RFA number "AI-01-006" and the words 
"Non-Human Primate Immune Tolerance Cooperative Study Group" must be entered on 
the face page.
 
The RFA label and line 2 of the application should both indicate the RFA number.  
The RFA label must be affixed to the bottom of the face page.  Failure to use 
this label could result in delayed processing of the application such that it 
may not reach the review committee in time for review.

The sample RFA label available at: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to 
allow for this change.  Please note this is in pdf format.

Submit a signed, typewritten original of the application, including the 
checklist, and three signed, exact, single-sided photocopies, in one package to:

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

At the time of submission, two additional exact copies of the grant application 
and all five sets of any appendix material must be sent to Dr. Priti Mehrotra at 
the address listed under “INQUIRIES.”  DUE TO THE EXPEDITED NATURE OF THIS RFA, 
IT IS VERY IMPORTANT TO SEND THESE ADDITIONAL COPIES IN ORDER TO FACILITATE THE 
PEER REVIEW PROCESS.

Applicants from institutions that have a Regional Primate Research Center (RPRC) 
funded by the NIH National Center for Research Resources may wish to identify 
these centers as resources for conducting the proposed research.  If so, a 
letter of agreement from the RPRC program director or principal investigator 
could be included with the application.

SPECIFIC INSTRUCTIONS FOR U01 COOPERATIVE AGREEMENT APPLICATIONS

If a U01 application submitted in response to this RFA is substantially similar 
to a grant application already submitted to the NIH for review, but that has not 
yet been reviewed, the applicant will be asked to withdraw either the pending 
application or the new one.  Simultaneous submission of identical applications 
will not be allowed, nor will different review committees review essentially 
identical applications.  Therefore, an application that is essentially identical 
to one that has already been reviewed cannot be submitted in response to this 
RFA.  This does not preclude the submission of substantial revisions of 
applications already reviewed, but such applications must include an 
introduction addressing the previous critique.

SPECIAL INSTRUCTIONS FOR U19 COOPERATIVE AGREEMENT APPLICATIONS IN RESPONSE TO 
THIS RFA	

Applicants for U19 cooperative agreements must follow special application 
guidelines in the NIAID Brochure entitled INSTRUCTIONS FOR APPLICATIONS FOR 
MULTI-PROJECT AWARDS (August 2000); this brochure is available via the web at: 
http://www.niaid.nih.gov/ncn/grants/multibron.htm. 

Applications that are not received as a single package on the receipt date or 
that do not conform to the instructions contained in PHS 398 (rev. 4/98) 
Application Kit (as modified in, and superseded by, the NIAID BROCHURE ENTITLED 
"INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS" for U19 awards) will be 
judged non-responsive and will be returned to the applicant.

Current NIH policy permits a component research project of a multi-project grant 
application to be concurrently submitted as a traditional individual research 
project (R01) application.  If, following review, both the multi-project 
application and the R01 application are found to be in the fundable range, the 
investigator must relinquish the R01 and will not have the option to withdraw 
from the multi-project grant.  This is an NIH policy intended to preserve the 
scientific integrity of a multi-project grant, which may be seriously 
compromised if a strong component project(s) is removed from the program.  
Investigators wishing to participate in a multi-project grant must be aware of 
this policy before making a commitment to the Principal Investigator and 
awarding institution.  However, concurrent submission of a component research 
project of a multi-project U19 cooperative agreement application as an 
individual U01 cooperative agreement application to this RFA is prohibited.

MINIMUM REQUIREMENTS FOR APPLICATION

To promote the development of a collaborative program among the award 
recipients, a minimum number of issues need to be addressed in the applications, 
as outlined below.

1.  The application must include a broad-based research program designed to 
evaluate the safety and efficacy of tolerogenic approaches in non-human primate 
models of asthma and allergic diseases, autoimmune diseases, kidney 
transplantation, or islet transplantation with the goal of inducing 
immunosuppression free immune tolerance and delineating the mechanisms involved 
in the induction, maintenance and loss of tolerance as an integral part of the 
treatment protocols.  U19 applications must contain more than one tolerogenic 
approach.  U01 applications may contain a single tolerogenic approach.  The 
research program shall include the following:

a) A discussion of the state-of-the-art of research focused on elucidating the 
underlying mechanisms of immune tolerance and on evaluating tolerogenic 
approaches in non-human primate studies and human clinical trials.

b) A description of gaps in knowledge and scientific opportunities relevant for 
the application of tolerogenic approaches to non-human primate studies and human 
clinical trials.

c) A plan to accelerate research on immune tolerance in non-human primate models 
of immune-mediated diseases, including:

o A conceptual framework delineating approaches to tolerance induction and 
their relevance to human immune-mediated diseases, priorities among the various 
approaches and the rationale for such priorities, including potentially 
promising reagents and molecules in development;
o A description of promising non-human primate treatment protocols, including 
the rationale for the selection of tolerogenic approaches and overall study 
design; and
o A description of promising mechanistic studies to be incorporated as an 
integral part of the non-human primate treatment protocols, including the 
rationale for the selection of the mechanistic studies, proposed techniques, and 
the overall design of such studies.
o A plan detailing the acquisition and preparation, if applicable, of the solid 
organs, tissues or cells to be used in the studies. All costs required for this 
must be included in the application and fully justified.

2.  The application must also include a 1-2 page synopsis (to be included as 
appendices) of the proposed treatment protocol(s) to assess safety and efficacy 
and incorporating the proposed mechanistic studies.  Since the actual study 
protocols to be performed will be selected by the Steering Committee, the final 
protocols implemented by the Cooperative Study Group may not reflect any 
protocol submitted in response to this RFA. Budget requests should reflect and 
fully justify all costs associated with the conduct of the above studies.

3.  U19 applications must include at least two proposed specific aims focused on 
the development, evaluation and validation of sensitive immune and/or surrogate 
biomarkers of the induction, maintenance, or loss of tolerance.  U01 
applications may include a single specific aim on the above.  Proposed tolerance 
assay studies are to include: identification of and rationale for the immune 
and/or surrogate markers selected, including published data from in vitro or in 
vivo studies; description of and rationale for the proposed source, quantity and 
number of samples required; methodologies proposed to collect and analyze 
samples; and a discussion of how the results of the proposed studies will 
contribute to improvements in the capacity to utilize immune and/or surrogate 
biomarkers to predict the induction, maintenance or loss of tolerance.  Use of 
new technologies, including minimally and non-invasive approaches, is 
encouraged.  Since the actual tolerance and/or surrogate biomarker assays to be 
performed will be selected by the Steering Committee, the final studies carried 
out by the Cooperative Study Group may not reflect any single study submitted in 
response to this RFA.  All costs required for the proposed tolerance and 
biomarker assays must be included in the application and must be fully 
justified.  These include the additional costs for data collection and analyses.

4.  For a U19 multi-project cooperative agreement, the application must identify 
the single applicant organization that will be legally and financially 
responsible and accountable for the use and disposition of funds awarded on the 
basis of this RFA to the applicant institution and other institutions 
participating in the consortium, if applicable, and show availability of 
personnel and facilities capable of performing and supporting the administrative 
functions necessary.  Essential elements of the multi-project cooperative 
agreement mechanism (U19) also include: (1) a minimum of three interrelated 
individual research projects organized around a central theme; (2) collaborative 
efforts and interaction among independent projects and their investigators to 
achieve a common goal; (3) a single Principal Investigator who will be 
scientifically and administratively responsible for the group effort; (4) a 
single applicant institution that will be legally and financially responsible 
for the use and disposition of funds awarded; and (5) where necessary, support 
for "Core" resources or facilities, each of which shall be utilized by at least 
two research projects in order to facilitate the research effort.  

5.  The application must name a single Principal Investigator (PI) who will have 
scientific responsibility for the application as a whole, including all 
consortium-related research activities, if applicable.  The PI must have 
substantial experience related to the scope and objectives of the RFA.  In 
addition, applications from a consortium of institutions must designate a single 
investigator for each participating institution who will be responsible for on-
site scientific implementation, direction and management of the studies, as well 
as the coordination of requirements for adjunct studies of underlying mechanisms 
and immune/surrogate markers.

6.  The application must also demonstrate the scientific and technical expertise 
required to design, conduct and analyze treatment protocols, mechanistic studies 
and assay development and validation.

7.  For a U19 multi-project cooperative agreement, the application must provide: 
a clear, concise plan, in narrative and diagrammatic form, that depicts the 
interrelationships among the research projects and the scientific and technical 
staff, their relevant experience/expertise, and the contribution of each to 
fulfillment of the objectives of this RFA; an organizational chart of the 
consortium showing the name, organization, and scientific discipline of the PI 
and of all key scientific, technical and administrative personnel; and a 
mechanism for selecting and replacing key professional or technical personnel.

8.  If the application is from a consortium of institutions, it must provide a 
plan to assure the maintenance of close cooperation and effective communication 
among members of the consortium, including letters of commitment to this plan 
from all participating institutions.

9.  The application must demonstrate the organization’s ability to participate 
effectively in cooperative, multi-center studies.  The application must also 
include a written commitment to: participating in the cooperative study group; 
serving on the Steering Committee and adhering to the decisions reached by that 
Committee, including following the consensus treatment protocols and adjunct 
studies; and accepting the participation and assistance of NIH staff in 
accordance with the guidelines outlined under "Terms and Conditions of Award: 
NIH Staff Responsibilities." 

10.  The application must include a written commitment to design and conduct 
non-human primate research, in addition to the studies funded in the initial 
application, under circumstances in which such additional research is of 
significant importance to further the field of immune tolerance.  Such 
circumstances include the evaluation of safety and efficacy and studies of 
underlying mechanisms for: existing tolerance induction treatment strategies in 
non-human primate models to produce data of critical importance to the design 
and conduct of scientifically sound and ethically acceptable human clinical 
trials; newly discovered molecular targets for the induction of immune tolerance 
identified through fundamental research in small animal models; and new non-
human primate models of kidney transplantation, islet transplantation for type 1 
diabetes, autoimmune diseases, and asthma and allergic diseases.  This written 
commitment must also include the awardee’s willingness and agreement to:  (1) 
prepare scientific proposals for the design, conduct and analysis of such 
additional studies and budget requests for all associated costs; (2) submit 
proposals for scientific evaluation by NIH staff and, when appropriate, non-
Federal experts identified by the sponsors of this research program; and (3) 
accept additional funding from NIH and non-Federal organizations to support such 
additional investigations.  The time frame within which such additional projects 
can be initiated and completed will be negotiated and agreed upon jointly 
between the awardees and the sponsors.

URLs in NIH Grant Applications or Appendices

All applications and proposals for NIH funding must be self-contained within 
specified page limitations.  Unless otherwise specified in an NIH solicitation, 
Internet addresses (URLs) should not be used to provide information necessary to 
the review because reviewers are under no obligation to view the Internet sites.  
Reviewers are cautioned that their anonymity may be compromised when they 
directly access an Internet site.

REVIEW CONSIDERATIONS

Review Procedures

Upon receipt, applications will be reviewed for completeness by the Center for 
Scientific Review (CSR) and for responsiveness by NIH staff.  Incomplete and/or 
non-responsive applications will be returned to the applicant without further 
consideration.  

Applications that are complete and responsive to the RFA will be evaluated for 
scientific and technical merit by an appropriate peer review group convened by 
the NIH in accordance with the review criteria and minimum requirements stated 
above.  As part of the initial merit review, all applications will receive a 
written critique and undergo a process in which only those applications deemed 
to have the highest scientific merit, generally the top half of applications 
under review, will be discussed, assigned a priority score, and receive a second 
level review by the National Council of the appropriate sponsoring institute.

Review Criteria

The criteria to be used in the evaluation of grant applications are listed 
below.  To put those criteria in context, the following information is contained 
in instructions to the peer reviewers.

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  The 
reviewers will comment on the following aspects of the application in their 
written critiques in order to judge the likelihood that the proposed research 
will have a substantial impact on the pursuit of these goals.  Each of these 
criteria will be addressed and considered by the reviewers in assigning the 
overall score weighting them as appropriate for each application.  Note that the 
application does not need to be strong in all categories to be judged likely to 
have a major scientific impact and thus deserve a high priority score.  For 
example, an investigator may propose to carry out important work that by its 
nature is not innovative but is essential to move a field forward.

1.  Significance.  Does this study address an important problem? If the aims of 
the application are achieved, how will scientific knowledge be advanced?  What 
will be the effect of these studies on the concepts or methods that drive this 
field?

2.  Approach.  Are the conceptual framework, design, methods, and analyses 
adequately developed, well integrated, and appropriate to the aims of the 
project?  Does the applicant acknowledge potential problem areas and consider 
alternative tactics? 

3.  Innovation.  Does the project employ novel concepts, approaches or method?  
Are the aims original and innovative? Does the project challenge existing 
paradigms or develop new methodologies or technologies? 

4.  Investigator.  Is the investigator appropriately trained and well suited to 
carry out this work?  Is the work proposed appropriate to the experience level 
of the principal investigator and other researchers (if any)?

5.  Environment.  Does the scientific environment in which the work will be done 
contribute to the probability of success?  Do the proposed experiments take 
advantage of unique features of the scientific environment or employ useful 
collaborative arrangements?  Is there evidence of institutional support?

The review criteria for U19 multi-project cooperative agreement applications are 
presented in the NIAID Brochure entitled INSTRUCTIONS FOR APPLICATIONS FOR 
MULTI-PROJECT AWARDS (August 2000); this brochure is available via the WWW at: 
http://www.niaid.nih.gov/ncn/grants/multibron.htm.  Applicants are instructed to 
consult this website for details on the criteria for evaluating of each project 
and core as well as the overall application.  Five review criteria listed above 
will be used to evaluate each project.  Review criteria for scientific cores 
consist of the following: justification and usefulness to the various research 
projects, relationship to the central focus of the overall program, quality of 
relevant services or facilities, qualifications of the personnel, and 
appropriateness of the budget.  In addition, the initial review group will 
examine the appropriateness of proposed project budget and duration, the 
provisions for the protection of animal subjects, and the safety of the research 
environment.

Schedule

Letter of Intent Receipt Date:  June 11, 2001
Application Receipt Date:       July 17, 2001
Scientific Review Date:         October-November 2001
Advisory Council Date:          February 2002
Earliest Award Date:            April 1, 2002

AWARD CRITERIA

Funding decisions will be made on the basis of scientific and technical merits 
determined by peer review, program balance, and the availability of funds. 

INQUIRIES

Written and telephone inquiries concerning this RFA are encouraged.  The 
opportunity to clarify any issues or questions from potential applicants is 
welcome.

Requests for the NIAID brochure "INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT 
AWARDS" as well as inquiries regarding programmatic (research scope and 
eligibility) issues, may be directed to:

Shiv A. Prasad, Ph.D.
Division of Allergy, Immunology and Transplantation
National Institute of Allergy and Infectious Diseases
6700-B Rockledge Dr., Room 5255
Bethesda, MD  20892-7640 (20817 for express mail deliveries)
Telephone:  (301) 496-5598
FAX:  (301) 402-2571
Email: sprasad@nih.gov

Joan T. Harmon, Ph.D.
Division of Diabetes, Endocrinology, and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Blvd., Room 697
Bethesda, MD 20892-5640 (20817 for express mail deliveries)
Telephone: 301-594-8813
FAX: 301-480-3503
Email: harmonj@ep.niddk.nih.gov

Direct inquiries regarding preparation of the application and review issues, 
address the letter of intent to, and mail two copies of the application and all 
five sets of appendices to:

Dr. Priti Mehrotra 
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6700-B Rockledge Dr., Room 2100
Bethesda, MD  20892-7616
Use Zip Code 20817 for overnight deliveries
Telephone:  (301) 435-9369
FAX:  (301) 402-2638
Email: pmehrotra@niaid.nih.gov

Direct inquiries regarding fiscal matters to:

Mollie Shea
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6700-B Rockledge Dr., Room 2247
Bethesda, MD  20892-7614
Use Zip Code 20817 for overnight deliveries
Telephone:  (301) 402-6576
FAX:   (301) 480-3780
Email: ms256g@nih.gov

Florence Danshes
National Institute of Diabetes and Digestive and Kidney Diseases
2 Democracy Plaza, MSC 5456
6707 Democracy Blvd.
Bethesda, MD  20892-5456
For Courier service, use Zip Code 20817
Telephone: (301) 594-8861
FAX: (301) 480-3504
Email: DANSHESF@EXTRA.NIDDK.NIH.GOV

AUTHORITY AND REGULATIONS

This program is described in the Catalogue of Federal Domestic Assistance No. 
93.855 – Immunology, Allergy, and Transplantation Research, No. 93.847 – 
Diabetes, Endocrinology and Metabolism Research, No 93.849 – Kidney Diseases, 
Urology and Hematology Research and No. 93.848 - Digestive Diseases and 
Nutrition Research.  Awards are made under authorization of Sections 301 and 405 
of the Public Health Service Act as amended (42 USC 241 and 284) and 
administered under NIH Grants policies and Federal Regulations 42 CFR 52 and 45 
CFR Parts 74 and 92.  This program is not subject to the intergovernmental 
review requirements of Executive Order 12372 or Health Systems Agency review.

The Public Health Service strongly encourages all grant and contract recipients 
to provide a smoke-free workplace and promote the non-use of all tobacco 
products. In addition, Public Law 103-227, the Pro-Children Act of 1994, 
prohibits smoking in certain facilities (or, in some cases, any portion of a 
facility) in which regular or routine education, library, day care, health care 
or early childhood development services are provided to children.  This is 
consistent with the PHS mission to protect and advance the physical and mental 
health of the American people. 


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