Full Text AI-93-07 MECHANISMS OF PERIPHERAL IMMUNOLOGICAL TOLERANCE AND ANERGY NIH GUIDE, Volume 21, Number 45, December 18, 1992 RFA: AI-93-07 P.T. 34 Keywords: Immunology Autoimmunity National Institute of Allergy and Infectious Diseases Letter of Intent Date: January 15, 1993 Application Receipt Date: March 25, 1993 PURPOSE The Division of Allergy, Immunology and Transplantation (DAIT) of the National Institute of Allergy and Infectious Diseases (NIAID) invites applications for studies dealing with the mechanisms of peripheral immunological tolerance and anergy. Improved knowledge of peripheral tolerance and anergy is likely to open new avenues to: treatment or prevention of a variety of autoimmune and allergic disorders, moderating organ and bone marrow graft rejection, and vaccination against infectious organisms. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This Request for Applications (RFA), Mechanisms of Peripheral Immunological Tolerance and Anergy, is related to the priority areas of diabetes and chronic disabling diseases, and to immunization and infectious diseases. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0) or "Healthy People 2000" (Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-782-3238). ELIGIBILITY REQUIREMENTS Only domestic organizations are eligible to apply. Applications may be submitted by domestic for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. The NIAID encourages the participation of minorities and women, either as the Program Director or as project leaders of the component research projects of the application. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) Program Project grant (P01). A P01 is awarded to an institution on behalf of a Program Director for the support of a broadly based, multidisciplinary, long-term research program with a specific major goal or central theme. A P01 generally involves the organized efforts of a group of investigators who conduct research projects related to the overall program goal. The grant may provide support for the projects and for certain central resources shared by individuals in the P01 if sharing facilitates the total research effort. Each project supported under a P01 is expected to contribute to and be directly related to the central theme of the program. The projects, each under the direction of a Project Leader, must demonstrate an essential element of unity and interdependence. The application should clearly explain how the projected multidisciplinary integrated program can be expected to accomplish the stated goal more efficiently and effectively than could a series of independent, individual grant-supported studies. Designation of a Principal Investigator as Program Director must be based upon accomplishment and experience as a scientist, the ability to assume both the leadership of the research group and the responsibility for scientific, professional, and administrative functions, and the commitment of a significant amount of his/her time to the project. Each research project in the program should have a designated Project Leader with a demonstrable record of accomplishment in immunology or one of the basic science disciplines or clinical specialties relevant to the particular subject of investigation. However, the NIAID encourages the designation as Project Leader of one junior investigator whose scientifically meritorious project is an integral part of the overall program and whose work would be closely related to that of one or more senior scientists of the P01. The total project period for applications submitted in response to this RFA may not exceed five years. At this time, the NIAID is administratively limiting the duration of such grants to four years; this administrative limitation may change in the future. The budget of the P01 application should not exceed $500,000 total direct costs in the first year and no more than four percent annual inflationary increases for future years. Applications with an annual budget request in excess of this amount will require written approval by senior NIAID officials via the program officer for acceptance of the application for processing. FUNDS AVAILABLE The estimated total funds (direct and indirect costs) available for the first year of support for this RFA will be $1,500,000. In Fiscal Year 1993, the NIAID plans to award at least two program project grants submitted in response to this RFA and, depending on availability of funds and scientific merit, possibly more than two. PHS policies governing grants administration and management will apply. This level of support is dependent on the receipt of a sufficient number of applications of high scientific merit. Although this program is provided for in the financial plans of the NIAID, 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 Tolerance and anergy may be imposed at any of several levels within the immune system and, while the precise mechanisms may vary, together these levels probably constitute a hierarchy that is designed to prevent normal physiological reactions against self from leading to autoimmune disorders. Thus, tolerance may arise from clonal deletion of potentially autoaggressive T cells within the thymus ("ignorance of self"). Alternatively, prospective T cells may be rendered nonfunctional ("anergic") within the thymus and subsequently be exported without dying. Similarly, extrathymic T cells may be eliminated by programmed cell death or rendered anergic, although still viable. Both B and T lymphocytes are susceptible to the induction of tolerance and anergy. Because central T cell nonresponsiveness appears at present to be receiving the most attention, this RFA is intended to promote research on the mechanisms leading to clonal deletion and functional inactivation of peripheral lymphocytes, both B and T. Research Objectives and Scope The goal of this program is to gain a comprehensive understanding of the nature of peripheral tolerance and anergy: what they are, how they are induced, and the biochemical and molecular genetic events involved in inducing and maintaining them. Studies that involve humans and human tissues and cells, are especially encouraged. The following are some examples of the questions about T lymphocytes that need to be addressed: o What are the elements (e.g., types of interacting cells, surface molecules, cytokines) and mechanisms involved in T cell tolerance and anergy that operate extrathymically? o Do the mechanisms that lead to tolerance and anergy differ depending on the tolerizing/anergizing stimulus? For example, would the mechanisms differ if a convential antigen or a super-antigen were involved or if the stimulus were a free peptide compared to a Class II-peptide complex? o What roles are played by the Ti-CD3 complex or by CD4 and CD8 accessory molecules in the induction of T cell tolerance? o Are CD4+ and CD8+ T cells distinguishable in their susceptibility to the induction of tolerance and anergy? o What are the different roles played by TH1 and TH2 cells and the spectra of cytokines that they secrete in the induction and maintenance of tolerance and anergy? The following are some examples of the questions about B lymphocytes that need to be addressed: o What is the importance of the density, distribution, affinity and isotype of membrane-bound antibody molecules? o Is B-cell anergy associated with the absence of stimuli/signals that would otherwise lead to B-cell activation and, if so, what is the nature of such stimuli? o What is the importance of the differentiative status of B cells in terms of the induction of tolerance and anergy? The prospects of important clinical applications calls for a concerted effort to acquire better understanding of these phenomena. STUDY POPULATIONS SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH STUDY POPULATIONS NIH policy requires that applicants for NIH clinical research grants and cooperative agreements include minorities and women in study populations so that research findings can be of benefit to all persons at risk of the disease, disorder or condition under study; special emphasis must be placed on the need for inclusion of minorities and women in studies of diseases, disorders and conditions which disproportionately affect them. This policy is intended to apply to males and females of all ages. If women or minorities are excluded or inadequately represented in clinical research, particularly in proposed population-based studies, a clear compelling rationale MUST be provided. The composition of the proposed study population must be described in terms of gender and racial/ethnic group, together with a rationale for its choice. In addition, gender and racial/ethnic issues should be addressed in developing a research design and sample size appropriate for the scientific objectives of the study. This information should be included in the form PHS 398 in items 1-4 of the Research Plan AND summarized in item 5, Human Subjects. Applicants are urged to assess carefully the feasibility of including the broadest possible representation of minority groups. However, NIH recognizes that it may not be feasible or appropriate in all research projects to include representation of the full array of United States racial/ethnic minority populations [i.e., Native Americans (including American Indians or Alaskan Natives), Asian/Pacific Islanders, Blacks, Hispanics]. The rationale for studies on single minority population groups should be provided. For the purpose of this policy, clinical research includes human biomedical and behavioral studies of etiology, epidemiology, (and preventive strategies), diagnosis, or treatment of diseases, disorders or conditions, including but not limited to, clinical trials. The usual NIH policies concerning research on human subjects also apply. Basic research or clinical studies in which human tissues cannot be identified or linked to individuals are excluded. However, clinical samples which may be coded for use by the applicant but could be identified by another source are not excluded. Every effort should be made and documented to include human tissues from women and racial/ethnic minorities when it is important to apply the results of the study broadly, and this should be addressed by applicants. If the required information is not contained within the application, the application will be returned. Peer reviewers will address specifically whether the research plan in the application conforms to these policies. If the representation of women or minorities in a study design is inadequate to answer the scientific question(s) addressed AND the justification for the selected study population is inadequate, it will be considered a scientific weakness or deficiency in the study design and will be reflected in assigning the priority score to the application. All applications for clinical research submitted to NIH are required to address these policies. NIH funding components will not award grants or cooperative agreements that do not comply with these policies. LETTER OF INTENT Prospective applicants are asked to submit, by January 15, 1993, a letter of intent that includes a descriptive title of the overall proposed research, the name, address and telephone number of the Principal Investigator (Program Director), the names of key investigators, their institution(s), 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 NIAID staff to estimate the potential review workload and to avoid conflict of interest in the review. The letter of intent is to be sent to Dr. Mark Rohrbaugh at the address listed under INQUIRIES. APPLICATION PROCEDURES Applications are to be submitted on the standard research grant application form PHS 398 (rev. 09/91). Item 2a on the face page of the application must be marked "yes" and the RFA number and the words MECHANISMS OF PERIPHERAL IMMUNOLOGICAL TOLERANCE AND ANERGY must be typed in. These application forms may be obtained from the institution's office of sponsored research and from the Office of Grants Inquiries, Division of Research Grants, National Institutes of Health, 5333 Westbard Avenue, Room 449, Bethesda, Maryland 20892, telephone (301) 496-7441. It is highly recommended that the Chief of the Basic Immunology Branch or the Chief of the Immunoregulation Section be contacted in the early stages of preparation of the application. Applications must be received by March 25, 1993. Applications that are not received by the receipt date or that do not conform to the instructions contained in PHS 398 (rev. 09/91) application kit, will be judged non-responsive and will be returned to the applicant. The RFA label available in the application form 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. Submit a signed, typewritten original of the application, including the checklist, and three signed, exact, single-sided photocopies, in one package to: Application Receipt Office Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** At the time of submission, two additional exact copies of the application must also be sent to Dr. Mark Rohrbaugh at the address under INQUIRIES. REVIEW CONSIDERATIONS General review considerations are outlined in the NIAID Information Brochure on Program Project and Center Grants, which contains special instructions for preparing multiproject applications for Program Projects. It includes REVIEW PROCEDURES and REVIEW CRITERIA for multicomponent, interdisciplinary projects and other important information. This Information Brochure and the RFA will be sent to applicants upon request. Upon receipt, applications will be reviewed for completeness by the Division of Research Grants (DRG) and for responsiveness by NIAID staff; those judged to be incomplete or non-responsive will be returned to the applicant without review. Those applications that are complete and responsive may be subjected to a triage by an NIAID peer review group before or during the scientific review meeting to determine their scientific merit relative to other applications received in response to this RFA. The NIAID will withdraw from competition those applications judged to be non-competitive for award and will notify the applicant and institutional business officials. Those applications judged by the reviewers to be competitive for award will be further reviewed for scientific and technical merit by a review committee convened by the Division of Extramural Activities, NIAID. The second level of review will be provided by the National Advisory Allergy and Infectious Diseases Council. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. If so, a letter of agreement from either the GCRC Program Director or the Principal Investigator of the GCRC must be included with the application. Review Criteria The general criteria are those review criteria for large, multicomponent, interdisciplinary program projects as outlined in the NIAID Brochure on Project Project and Center Grants. AWARD CRITERIA Funding decisions will be made on the basis of scientific and technical merit as determined by peer review, program needs and 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. Direct inquiries about the RFA and programmatic issues to: Joseph F. Albright, Ph.D. or M. Michele Hogan, Ph.D. Division of Allergy, Immunology and Transplantation National Institute of Allergy and Infectious Diseases Solar Building, Room 4A22 Bethesda, MD 20892 Telephone: (301) 496-7551 FAX: (301) 402-0175 Direct inquiries regarding review issues, and address the letter of intent to: Mark Rohrbaugh, Ph.E., Scientific Review Administrator Microbiology and Immunology Review Section Division of Extramural Activities National Institute of Allergy and Infectious Diseases Solar Building, Room 4C22 Bethesda, MD 20892 Telephone: (301) 496-8424 FAX: (301) 402-2638 Direct inquiries regarding fiscal matters to: Mr. Jeffrey Carow Chief, Immunology Grants Management Section Division of Extramural Activities National Institute of Allergy and Infectious Diseases Solar Building, Room 4B92 Bethesda, MD 20892 Telephone: (301) 496-7075 The mailing address for sending applications to NIAID staff in the Solar Building is the central mailing address for NIH. Applicants who use express mail or a courier service are advised to follow the carrier's requirements for showing a street address. The address for the Solar Building is: 6003 Executive Boulevard Rockville, MD 20852 Schedule Letter of Intent Date: January 15, 1993 Application Receipt Date: March 25, 1993 Scientific Review Date: June 1993 Advisory Council Date: September 1993 Earliest Award Date: September 1993 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance, No. 93.855 - Immunology, Allergy and Transplantation Research. Awards will be made under the authority of the Public Health Service Act, Title III, Section 301 (Public Law 78-410, as amended; 42 USC 241) and administered under PHS grants policies and Federal Regulations 42 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. .
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