Full Text PA-97-075 DIRECT VS INDIRECT ANTIGEN RECOGNITION IN ALLOGRAFT SURVIVAL NIH GUIDE, Volume 26, Number 24, July 25, 1997 PA NUMBER: PA-97-075 P.T. 34 Keywords: Transplantation Immunology Transplantation of Organs National Institutes of Health PURPOSE The National Institutes of Health invites applications for studies to further our understanding of the immune response to direct or indirect presentation of allogeneic major histocompatibility complex (MHC) antigens and to determine the contribution of each pathway to acute and chronic graft rejection. Research to date has focused on direct recognition of allogeneic MHC and therapies designed to block this pathway have been successful in reducing acute rejection of transplanted organs. However, chronic rejection is still an impediment to long-term survival. The indirect pathway of allorecognition has recently been implicated primarily in chronic graft rejection, however an additional role for this pathway in the enhancement of acute rejection has been suggested. Knowledge from basic, preclinical and clinical studies aimed at characterizing the relative role of the direct and the indirect allorecognition pathways in enhancing or preventing graft rejection could lead to the development of specific interventions to modulate immune recognition after transplantation and ultimately increase graft survival. HEALTHY PEOPLE 2000 Each NIH PA addresses one or more of 22 Health Promotion and Disease Prevention priority areas identified. These areas can be found via the WWW at URL: http://www/crisny.org/health/us/health7.html ELIGIBILITY Applications may be submitted by domestic and foreign, 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. Foreign institutions are not eligible for First Independent Research Support and Transition (FIRST) (R29) awards. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT Traditional research project grant (R01)and FIRST award (R29) applications may be submitted in response to this program announcement. Applications for R01 grants may request up to five years of support; applications for R29 grants must request five years of support. Responsibility for the planning, direction, and execution of the proposed research for all applicable mechanisms of support will be solely that of the applicant. RESEARCH OBJECTIVES Background Recognition of allogeneic major histocompatibility complex (MHC) antigens is still a major impediment to the survival of solid organ grafts. Although progress has been made in the short-term survival of transplants, immunologic rejection is still an impediment to long-term survival. Direct recognition of allogeneic (MHC) antigens by T cells had been thought to be the primary cause of acute rejection of transplanted organs. Indirect recognition results from self MHC-restricted presentation of donor MHC peptides and occurs when the allogeneic MHC molecules shed by the donor tissue are taken up and processed by recipient antigen presenting cells (APC). This pathway has recently been implicated in the chronic rejection of transplanted organs. The mechanism(s) of rejection mediated by either direct or indirect recognition are likely to be different. The direct recognition pathway involves recognition by recipient T cells of donor allogeneic MHC class I and class II, resulting in the generation of cytotoxic and helper T lymphocytes which play a pivotal role in the rejection process. For indirect recognition, the precise mechanism(s) by which recognition of self MHC-restricted, donor MHC peptides initiates or enhances rejection is not understood since the antigenic MHC-peptide complex that is recognized is not present on the donor tissue. Some evidence suggests that indirect recognition of donor MHC can provide help for and thus amplify the acute rejection mediated by direct recognition. Thus the relative contribution of direct and indirect antigen presentation to acute and chronic rejection is still an unresolved issue. Although recognition of alloantigen can lead to deleterious effects on a graft, there are several examples of tolerance induction following exposure of the recipient to donor alloantigen prior to transplantation, either by infusion with whole cells or by treatment with MHC-derived synthetic peptides. The success of this strategy is dependent upon the nature and dose of the antigen as well as the route of administration. Further investigation is needed to determine how to control the balance between activation and unresponsiveness mediated by the direct and/or indirect recognition of alloantigen. Thus additional research is needed to distinguish the contributions of direct and indirect recognition to allograft survival and to determine how this knowledge could lead to improvements in existing therapies as well as the development of new therapies to prolong graft survival. Research Objectives and Scope This research focuses on understanding the specificity of T cell recognition of allogeneic MHC molecules in the transplant setting. These recognition events are key to understanding subsequent events leading to allograft rejection and are thus the focal point for immunotherapeutic intervention aimed at preventing immunologic rejection of organ and tissue grafts. The scope of research to be supported under this PA includes, but is not limited to, the following specific examples of investigation. The examples are meant to illustrate areas that remain to be investigated. Investigators are encouraged to develop novel approaches to study the relative contributions of direct and indirect alloantigen recognition and their role(s) in the rejection of transplanted organs. Specific areas of interest include, but are not limited to: o analysis of the contribution of indirect alloantigen recognition in the initiation and/or amplification of acute and chronic graft rejection; o identification of the antigen presenting cells involved in direct and indirect presentation and the nature of the T cell responses that are generated; o development of methods to specifically modulate the indirect antigen recognition pathway to prevent graft rejection, including combined strategies to modulate both direct and indirect recognition; o definition and molecular characterization of tolerance induction by pretreatment with alloantigen or alloantigen-derived peptides; and o effect of delayed antigen recognition on activation of the direct or indirect pathway in acute and chronic rejection. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS See NIH Guide of March 18, 1994 for requirements for inclusion of Women and Minorities in research. It is available via the WWW at URL: http://www.nih.gov/grants (select NIH Guide for Grants and Contracts). APPLICATION PROCEDURES Applications are to be submitted on the grant application for PHS 398 (rev. 5/95) and will be accepted on the standard application deadlines as indicated on the application kit. Application kits are available at most institutional offices of sponsored research and may be obtained from the Office of Extramural Outreach and Information, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone (301) 710-0267, email: asknih@odrockm1.nih.gov. The PHS 398 application kit can be accessed from the World Wide Web at the following URL: http://www.nih.gov/grants/funding/phs398/phs398.html. For purposes of identification and processing, item 2 on the face page of the application must be marked "YES". The PA number and the title must also be typed in section 2. The completed, signed original and five legible, single-sided copies of the application must sent or delivered to: DIVISION OF RESEARCH GRANTS NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817-7710 (for express/courier service) FIRST (R29) award applications must include at least three sealed letters of reference attached to the face page of the original application. FIRST applications submitted without the required number of reference letters will be considered incomplete and will be returned without review. Applicants from institutions that have a General Clinical Research Centers (GCRC) funded by the NIH National Center for Research Resources may wish to identify the Center as a resource for conducting the proposed research. If so, a letter of agreement from the GCRC Program Director must be included in the application material. REVIEW CONSIDERATIONS Review Procedures Applications will be assigned on the basis of established PHS referral guidelines. Upon receipt, applications will be reviewed for completeness by the NIH Division of Research Grants. Incomplete applications and applications deemed unresponsive will be returned to the applicant without further consideration. Applications will be reviewed for scientific and technical merit by study sections of the Division of Research Grants, NIH, in accordance with the standard NIH peer review procedures. 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 the applications under review, will be discussed, assigned a priority score, and receive a second level review by the appropriate national advisory council. Review Criteria The five criteria to be used in the evaluation of grant applications are listed below. 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 be asked to comment on the following aspects of the application 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 initial review group will also examine: the appropriateness of proposed project budget and duration; the adequacy of plans to include both genders and minorities and their subgroups as appropriate for the scientific goals of the research and plans for the recruitment and retention of subjects; the provisions for the protection of human and animal subjects; and the safety of the research environment. AWARD CRITERIA Applications will compete for available funds with all other favorably recommended applications. The following will be considered when making funding decisions: quality of the proposed project as determined by peer review, program balance, and availability of funds. INQUIRIES Each sponsoring Institute/Center is identified below. A staff contact for electronic and telephone is listed and inquiries regarding programmatic (research scope, eligibility and responsiveness) issues are encouraged. The opportunity to clarify any issues or answer questions from potential applicants is welcome. National Institute of Allergy and Infectious Diseases Janet M. Connolly, Ph.D. Telephone: (301) 496-5598 Fax: (301) 402-2571 EMAIL: jc333b@nih.gov National Heart Lung and Blood Institute LeeAnn Jensen, Ph.D. Telephone: (301) 435-0066 Fax: (301) 480-1060 Email: lj15x@nih.gov National Institute of Diabetes and Digestive and Kidney Diseases Lawrence Agodoa, M.D. Fax: (301) 480-3510 Email: agodoal@ep.niddk.nih.gov National Institute of Arthritis and Musculoskeletal and Skin Diseases Susana Serrate-Sztein, M.D. Telephone: (301) 594-5032 FAX: (301) 480-4543 Email: szteins@ep.niams.nih.gov AUTHORITY AND REGULATIONS Research under this announcement will be supported under programs cited in the Catalog of Federal Assistance (CFDA). The PHS portion of the CFDA is available at URL: http://odphp.osophs.dhhs.gov/cfda/index.htm Awards will be administered under PHS grants policies and Federal Regulations 42 CFR Part 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems review. The Public Health Service strongly encourages all grant recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. .
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