Full Text PA-97-077 MINOR HISTOCOMPATIBILITY ANTIGENS IN GVHD & GRAFT REJECTION NIH GUIDE, Volume 26, Number 24, July 25, 1997 PA NUMBER: PA-97-077 P.T. 34 Keywords: Immunology Transplantation Immunology National Institutes of Health PURPOSE The National Institutes of Health (NIH) invites applications for studies to further our understanding of the role of minor histocompatibility antigens (MiHA) in graft vs host disease (GVHD) following bone marrow transplantation and the possible involvement of MiHAs in chronic graft rejection of solid organ transplants. Most of the research efforts to date have centered on the role of the major histocompatibility complex (MHC) antigens in rejection of transplanted tissues and organs. This Program Announcement is directed at characterizing the immunologic response to MiHA and at defining the manner and extent to which that response affects successful long-term engraftment. The immune response to MiHA is a major, if under appreciated, cause of graft failure in bone marrow transplantation. This initiative is designed to promote research to characterize the immunologic response to MiHA and to attempt to define how that response can be prevented to enhance graft survival. It will support basic, pre-clinical, and clinical studies using molecular and cellular approaches to dissect the immune response to these antigens. These studies may lead to new information with the potential for clinical applications thereby improving long-term graft survival in bone marrow and solid organ transplant recipients. 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) awards (R29). Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISMS OF SUPPORT Traditional research project grant (R01) and FIRST award (R29) applications may be submitted in response to this announcement. Applications for R01 grants may request up to five (5) 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 Transplantation of bone marrow and solid organs such as kidney, heart, liver and lung remains the treatment of choice for several disease states. Although recent progress has improved the short-term survival of allografts, immunological rejection is still an impediment to long-term survival. Substantial evidence has been accumulated indicating that matching the donor organ and the patient for major histocompatibility complex (MHC) antigens can improve both solid organ and bone marrow graft survival. However little is known about the extent to which minor histocompatibility antigen (MiHA) mis-matches affect graft survival. For example, in patients who have been treated to prevent graft rejection, approximately half of HLA-matched bone marrow recipients develop acute or chronic GVHD and this is believed to result from MiHA mis-matches. Similarly, while short-term solid organ transplant survival is positively affected by MHC matching, long-term graft survival is still poor with only 40% of kidneys surviving more than ten years. The role of MiHA mis-matches in the eventual loss of these grafts is unknown and the subject of controversy. The total number of MiHA loci is unknown and evidence from several laboratories suggests that there are a limited number of minor antigenic differences between individuals. It is noteworthy that even an allelic difference, involving a single conservative amino acid substitution in a normal protein, can change it into a minor antigen. A major impediment to the identification and characterization of the MiHA antigens is that they are not recognized by B cells, resulting in the inability to produce antibodies to them. The MiHA do, however, stimulate T cell responses. The nature of the T cells that are stimulated is an area that requires further investigation and appears to depend on the specific MiHA that is being recognized. For example, whereas MHC class I-restricted CD8+ T cells have been generated against numerous MiHa, MHC class II-restricted responses have been generated against only a limited number of MiHA. In addition, although most of the CD8+ responses can involve class II-restricted, CD4+ T cell help, several MiHA have been reported to stimulate T helper cell-independent responses. It is not known to what extent the different types of responses impact bone marrow or solid organ graft survival. Recent advances in the analysis of MiHA has revealed that the antigens appear to be MHC class I bound small peptides presented to alpha-beta T cell receptor (TCR)+ T cells in an MHC-restricted manner. Thus, MiHA are recognized with the same degree of specificity as the major histocompatibility antigens. Also, recent studies imply that only a few of the many identified MiHA are recognized in an allotransplant setting, suggesting that there are immuno-dominant MiHA. While the relative tissue expression of MiHA has not been determined, due to the lack of available reagents, functional analyses using cytotoxic T cells suggest that many MiHA have a tissue restricted distribution and, thus, only certain tissues may be at risk for rejection. Also of interest is the observation that, in bone marrow transplantation, the clinical picture of MiHA GVHD resembles several autoimmune diseases, such as systemic lupus erythematosis and scleroderma, suggesting that the symptoms of chronic GVHD are autoimmune-like. As can be seen from the above discussion, the immune response to MiHAs is complex and therefore basic, pre-clinical, and clinical research will be required to further understand MiHAs and their involvement in GVHD and solid organ graft rejection. Research Objectives and Scope The objectives of this PA are to identify and characterize MiHA and to determine their role in GVHD and rejection of solid organ grafts. This information will be used to identify approaches to enhance graft survival and to test them experimentally. The scope of research to be supported under this PA includes, but is not limited to, the following broad areas of interest and specific examples of investigations. The examples are not meant to be directive, but illustrative of areas that remain to be further investigated. Therefore, investigators are encouraged to develop novel approaches to identify and characterize MiHA and the immune response to them. Relevant topics include, but are not limited to: o Identification of the genetic loci that encode MiHA and establishment of techniques to determine the total number of minor loci. o Identification of immunodominant minor antigens and their antigenic peptides and the mechanism of immunodominance (relative abundance, affinity of peptide for MHC, affinity of TCR for MHC/MiHA peptide complex). Also, in vivo correlates of in vitro peptide immunodominance could be studied to determine if the immunodominant peptides identified in vitro function similarly in vivo. o Analysis of TCR gene usage by responding T cells to determine if there is heterogeneity or preferential usage in the responding T cell population. Correlation of TCR usage with recognition of an immunodominant antigen. o Studies of the relative tissue expression of various MiHA and the impact of differential tissue distribution on transplant rejection. o Latent viral antigens as a potential source of MiHA. o Functional analysis of MiHA-reactive CD8+ T cells and studies of the role of CD4+ T cells in the anti-MiHA response. Differences between MiHA antigens that stimulate CD8+ vs CD4+ responses. 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 PA title must also be typed in section 2. The completed, signed original and five legible, single-sided copies of the application must be 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) R29 applications must include at least three (3) 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 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. SPONSORS AND 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 Cancer Institute For NCI basic research: Anne K. Heath Telephone: (301) 496-7815 Fax: (301) 496-8656 Email: ah43v@nih.gov For NCI Clinical Research: Roy Wu, Ph.D. Telephone: (301) 496-8866 Fax: (301) 480-4663 Email: WuR@dct.nci.nih.gov National Institute of Diabetes and Digestive and Kidney Diseases Lawrence Agodoa, M.D. Telephone: (301) 594-7717 Fax: (301) 480-3510 Email: agodoal@ep.niddk.nih.gov AUTHORITY AND REGULATIONS Research under this announcement will be supported under program 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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