ANIMAL MODELS OF ORGAN-SPECIFIC TOLERANCE FOR HEART AND LUNG TRANSPLANTATION

RELEASE DATE:  January 7, 2002

PA NUMBER:  PA-02-044

EXPIRATION DATE:  March 1, 2005, unless reissued.

PARTICIPATING INSTITUTES AND CENTERS (ICs):

National Heart, Lung, and Blood Institute (NHLBI)
 (http://www.nhlbi.nih.gov)

THIS PA CONTAINS THE FOLLOWING INFORMATION:

o Purpose of the PA
o Research Objectives
o Mechanism(s) of Support 
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Where to send Inquiries
o Submitting an Application
o Peer Review Process
o Review Criteria
o Award Criteria
o Required Federal Citations

PURPOSE OF THIS PA

The purpose of this Program Announcement (PA) is to encourage the submission 
of applications for the development organ-specific tolerance protocols using 
1) large animal models for heart transplantation, and 2) both large and small 
animal models for lung transplantation.  The long-range goal is to provide 
animal models that may be used for preclinical studies of immune tolerance 
induction, specifically in heart or lung studies, and improve the long-term 
quality of life and survival of recipients of heart and lung transplants.

RESEARCH OBJECTIVES

Transplantation is the only successful therapy for end-stage heart or lung 
failure.  While the current one-year survival rate for heart and lung 
transplant recipients (85% and 77% respectively) is very good, it depends on 
life-long use of drugs powerful enough to prevent the immune system from 
rejecting the transplanted organ.  Moreover, long-term use causes 
nephrotoxicity and increased susceptibility to serious infections and 
malignancies.  In addition, although immunosuppressive agents are relatively 
effective at preventing acute rejection, patients still frequently develop 
chronic rejection.  Chronic rejection in heart transplants, manifested as 
transplant allograft vasculopathy, is the primary cause of the low five-year 
survival (68%) in patients who escape acute rejection.  In lung transplants, 
chronic rejection presents as obliterative bronchiolitis, which is the main 
factor contributing to the dismal 44% five-year survival for lung 
transplant recipients.

All transplant patients would benefit enormously if a state of specific 
immune tolerance could be induced.  The induction of tolerance could greatly 
reduce the medical, personal, and economic burden of immunosuppressive 
therapy as well as the high mortality associated with chronic rejection.  
Indeed, selective suppression of immunity to "non-self" antigens on the 
transplanted organ with retention of normal immune function is the ultimate 
goal of transplantation immunology.

In rodent models, numerous strategies have been used successfully to induce 
tolerance to heart transplantation.  However, in terms of heart 
transplantation, these strategies have not been reproducible in large animal 
models, such as non-human primates or miniature swine.  Although the rodent 
is an economical model for identifying strategies of tolerance induction, its 
immune system may be too different from that of the human to serve as a pre-
clinical model.  For example, 1) the age-related decline in T cell 
regeneration is much greater in humans than in mice, 2) the role of the 
interleukin receptor common ? chain differs between mice and primates; and 3) 
B cell and T cell development responds to different regulatory factors in 
these two species.  Ethical considerations require a more suitable pre-
clinical model to more accurately predict how the protocol will work in 
humans.  Thus, a large animal model, with an immune system more reflective of 
the human immune system, is essential for testing heart and lung tolerance 
protocols before moving into clinical studies.  The primary focus for immune 
tolerance in lung transplantation at present, however, is to develop 
protocols in small animal models that can be moved into large animals.  

This PA seeks to encourage multidisciplinary research that will focus on 
elucidating methods and mechanisms of antigen-specific tolerance induction 
and maintenance in clinically relevant animal transplant models.  Both small 
and large animal models are appropriate for studies investigating tolerance 
in the lung.  Heart studies should use only large animal models.  Human 
studies are not appropriate for the scope of this PA.  Specific examples of 
areas of research interest may include, but are not restricted to, 
the following:

o Definition and manipulation of specific immune pathways involved in the 
induction and maintenance of antigen-specific tolerance, including:  co-
stimulatory pathways, cytokine modulation, the role of adhesion molecules, 
and leukocyte migration.

o Identification of allo-reactive lymphocytes subsets and their correlation 
with functions such as inflammation, homing and migration.

o Determination and validation of biomarkers of antigen-specific immune 
tolerance.

o Studies of the genetics of tolerance induction and long-term maintenance of 
tolerance.

o Elucidation of the molecular, biochemical and cellular mechanisms involved 
in the loss of antigen-specific tolerance.

o Use of very young animals to determine whether it is easier to induce 
tolerance in a young animal before the immune system is mature.

MECHANISM(S) OF SUPPORT 

This PA will use the NIH research project grant (R01) award mechanism.  As an 
applicant, you will be solely responsible for planning, directing, and 
executing the proposed project. The total project period for an application 
submitted in response to this PA may not exceed five years.

This PA uses just-in-time concepts.  It also uses the modular as well as the 
non-modular budgeting formats 
(see http://grants.nih.gov/grants/funding/modular/modular.htm).  Specifically, 
if you are submitting an application with direct costs in each year of $250,000 
or less, use the modular format.  Otherwise follow the instructions for non-
modular research grant applications.

ELIGIBLE INSTITUTIONS 

You may submit (an) application(s) if your institution has any of the 
following characteristics: 
	
o For-profit or non-profit organizations 
o Public or private institutions, such as universities, colleges, hospitals, 
and laboratories 
o Units of State and local governments
o Eligible agencies of the Federal government  
o Domestic or foreign

INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS

Any individual with the skills, knowledge, and resources necessary to carry 
out the proposed research is invited to work with their institution to 
develop an application for support.  Individuals from underrepresented racial 
and ethnic groups as well as individuals with disabilities are always 
encouraged to apply for NIH programs.   

WHERE TO SEND INQUIRIES

We encourage your inquiries concerning this PA and welcome the opportunity 
answer questions from potential applicants.  Inquiries may fall into three 
areas:  scientific/research, peer review, and financial or grants 
management issues:

o Direct your questions about scientific/research issues to:

For heart transplantation:

Judith Massicot-Fisher, PhD
Division of Heart and Vascular Disease
National Heart, Lung, and Blood Institute
Rockledge II, Room 9184
Bethesda, MD  20892-7940
Telephone:  (301) 435-0528
FAX:  (302) 480-1454
E-mail:  Massicoj@nih.gov

For lung transplantation:

Dorothy Gail, Ph.D.
Program Director
Lung Biology and Diseases Program
Division of Lung Diseases
National Heart, Lung and Blood Institute
Rockledge II, Room 10100
Bethesda, MD  20892-7952
Telephone:  (301) 435-0222
FAX:  (301) 480-3557
E-mail:  GailD@nih.gov

o Direct your questions about financial or grants management matters to:

Ms. Tanya McCoy
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Rockledge II, Room 7154
Bethesda, MD  20892-7926
Telephone:  (301) 435-0171
FAX:  (301) 480-3310
Email:  McCoyT@nih.gov

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001).  The PHS 398 is available at 
http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive 
format.  For further assistance contact GrantsInfo, Telephone (301) 435-0714, 
Email:  GrantsInfo@nih.gov.

APPLICATION RECEIPT DATES: Applications submitted in response to this program 
announcement will be accepted at the standard application deadlines, which 
are available at http://grants.nih.gov/grants/dates.htm.  Application 
deadlines are also indicated in the PHS 398 application kit.

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS:  Applications 
requesting up to $250,000 per year in direct costs must be submitted in a 
modular grant format.  The modular grant format simplifies the preparation of 
the budget in these applications by limiting the level of budgetary detail.  
Applicants request direct costs in $25,000 modules.  Section C of the 
research grant application instructions for the PHS 398 (rev. 5/2001) at 
http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step 
guidance for preparing modular grants.  Additional information on modular 
grants is available at 
http://grants.nih.gov/grants/funding/modular/modular.htm.

SPECIFIC INSTRUCTIONS FOR APPLICATIONS REQUESTING $500,000 OR MORE PER YEAR:  
Applications requesting $500,000 or more in direct costs for any year must 
include a cover letter identifying the NIH staff member within one of NIH 
institutes or centers who has agreed to accept assignment of the application.  
NHLBI 'Guidelines for Applications with Direct Costs of $500,000 or More in 
Any One Year' may be found at:  
http://www.nhlbi.nih.gov/funding/policies/500kweb.htm.
             
Applicants requesting more than $500,000 must carry out the following steps:
	
1) Contact the IC program staff at least 6 weeks before submitting the 
application, i.e., as you are developing plans for the study; 

2) Obtain agreement from the IC staff that the IC will accept your 
application for consideration for award; and,
  
3) Identify, in a cover letter sent with the application, the staff member 
and IC who agreed to accept assignment of the application.  

This policy applies to all investigator-initiated new (type 1), competing 
continuation (type 2), or any amended or revised version of these grant 
application types. Additional information on this policy is available in the 
NIH Guide for Grants and Contracts, October 19, 2001 at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html. 

SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of 
the application, including the checklist, and five signed 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)

APPLICATION PROCESSING: Applications must be received by or mailed before the 
receipt dates described at 
http://grants.nih.gov/grants/funding/submissionschedule.htm.  The CSR will 
not accept any application in response to this PA that is essentially the 
same as one currently pending initial review unless the applicant withdraws 
the pending application.  The CSR will not accept any application that is 
essentially the same as one already reviewed.  This does not preclude the 
submission of a substantial revision of an application already reviewed, but 
such application must include an Introduction addressing the previous 
critique.

PEER REVIEW PROCESS

Applications submitted for this PA will be assigned on the basis of 
established PHS referral guidelines.  An appropriate scientific review group 
convened in accordance with the standard NIH peer review procedures 
(http://www.csr.nih.gov/refrev.htm) will evaluate applications for scientific 
and technical merit.  

As part of the initial merit review, all applications will:

o Receive a written critique
o Undergo a selection process in which only those applications deemed to have 
the highest scientific merit, generally the top half of applications under 
review, will be discussed and assigned a priority score
o Receive a second level review by the appropriate national advisory council 
or board
	
REVIEW CRITERIA

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  In 
the written comments, reviewers will be asked to discuss the following 
aspects of your application in order to judge the likelihood that the 
proposed research will have a substantial impact on the pursuit of these goals: 

o Significance 
o Approach 
o Innovation
o Investigator
o Environment
  
The scientific review group will address and consider each of these criteria 
in assigning your application's overall score, weighting them as appropriate 
for each application.  Your application does not need to be strong in all 
categories to be judged likely to have major scientific impact and thus 
deserve a high priority score.  For example, you 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 your study address an important problem? If the aims 
of your application are achieved, how do they advance scientific knowledge?  
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?  Do you acknowledge potential problem areas and consider alternative 
tactics?

(3) INNOVATION:  Does your project employ novel concepts, approaches or 
methods? Are the aims original and innovative?  Does your project challenge 
existing paradigms or develop new methodologies or technologies?

(4) INVESTIGATOR: Are you appropriately trained and well suited to carry out 
this work?  Is the work proposed appropriate to your experience level as the 
principal investigator and to that of other researchers (if any)?

(5) ENVIRONMENT:  Does the scientific environment in which your 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?

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your 
application will also be reviewed with respect to the following:

PROTECTIONS:  The adequacy of the proposed protection for humans, animals, or 
the environment, to the extent they may be adversely affected by the project 
proposed in the application.

BUDGET:  The reasonableness of the proposed budget and the requested period 
of support in relation to the proposed research.

AWARD CRITERIA

Applications submitted in response to a PA will compete for available funds 
with all other recommended applications.  The following will be considered in 
making funding decisions:  

o Scientific merit of the proposed project as determined by peer review
o Availability of funds 
o Relevance to program priorities

REQUIRED FEDERAL CITATIONS 

PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The 
Office of Management and Budget (OMB) Circular A-110 has been revised to 
provide public access to research data through the Freedom of Information Act 
(FOIA) under some circumstances.  Data that are (1) first produced in a 
project that is supported in whole or in part with Federal funds and (2) 
cited publicly and officially by a Federal agency in support of an action 
that has the force and effect of law (i.e., a regulation) may be accessed 
through FOIA.  It is important for applicants to understand the basic scope 
of this amendment.  NIH has provided guidance at 
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.

Applicants may wish to place data collected under this PA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application should 
include a description of the archiving plan in the study design and include 
information about this in the budget justification section of the 
application.

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.   Furthermore, 
we caution reviewers that their anonymity may be compromised when they 
directly access an Internet site.

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 PA 
is related to one or more of the priority areas. Potential applicants may 
obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople.

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance No. 93.837 and 93.838 and is not subject to the 
intergovernmental review requirements of Executive Order 12372 or Health 
Systems Agency review.  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 described at 
http://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 
42 CFR 52 and 45 CFR Parts 74 and 92. 

The PHS strongly encourages all grant recipients to provide a smoke-free 
workplace and discourage the 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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