Full Text PA-97-089 MECHANISMS OF THE IMMUNE RESPONSE TO XENOTRANSPLANT ANTIGENS NIH GUIDE, Volume 26, Number 26, August 8, 1997 PA NUMBER: PA-97-089 P.T. 34 Keywords: 0705048 Transplantation Immunology Transplantation of Organs National Institute of Allergy and Infectious Diseases National Institute of Diabetes and Digestive and Kidney Diseases National Heart, Lung and Blood Institute PURPOSE The National Institute of Allergy and Infectious Diseases (NIAID), the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and the National Heart, Lung and Blood Institute (NHLBI) invite applications to enhance our ability to transplant organs and tissues across species barriers (xenotransplantation) by increasing our understanding of: the human immune response to antigens present on the surface of organs or tissues from non-human species, and the development of methods to allow rapid identification and treatment of infectious diseases that might occur by transmission of disease causing organisms across species barriers. This research would lead to the development of new therapies to allow xenografts to survive and function in humans and the generation of new, sensitive detection methods to decrease the risk of infectious disease associated with xenotransplantation. 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 Program Announcement (PA), Mechanisms of the Immune Response to Xenotransplant Antigens, is related to the priority areas of immunization and infectious diseases, diabetes and chronic disabling disease, and heart disease and stroke. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-0325 (telephone 202-512-1800). ELIGIBILITY REQUIREMENTS 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) grants. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT Traditional research project grants (R01) and FIRST award (R29) applications may be submitted in response to this PA. 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 Annually, there are more than 40,000 patients waiting for transplants of kidneys (35,000+), hearts (3,500+), and lungs (2,000+). In 1995, 19,100 people received transplants of these organs and, currently, there are shortages of all organs. Nine patients per day die waiting for an organ transplant. The shortage of human organs has led the transplant community to examine the possibility of using non-human organs. The first modern attempt at cross-species organ transplantation was in 1964, transplanting kidneys from chimpanzees into patients with renal failure. While the transplanted kidneys functioned initially, patients experienced acute rejection and infectious complications. One patient survived with a functioning chimpanzee kidney for nine months. The same year, a series of baboon-to-human kidney transplants was attempted with the same results, acute rejection and infection. The kidneys functioned while the patients remained alive. Twenty years later, the Baby Fae baboon heart transplant was attempted, using the new, highly effective immunosuppressive agent Cyclosporin A. Still, the heart failed after 20 days due to acute rejection. Other isolated cases of clinical xenotransplantation have been attempted, all leading to graft failure or patient death due to infection. Due to worries about transmission of infectious organisms, especially viruses, from non-human primates to humans, the pig may become the organ donor of choice. However, there are major problems to overcome. Humans have preformed antibodies called xenoreactive natural antibodies (XNA). These XNA include IgM, IgG and IgA and appear in the early neonatal period following coliform bacterial colonization of the large bowel. Most XNA recognize bacterial cell wall associated carbohydrates, and are reactive primarily against the terminal Gal-alpha-1,3-Gal moiety. These XNA mediate hyperacute rejection (HAR) of pig organs transplanted in non-human primates via activation of complement. The hallmarks of the HAR are hemorrhage, widespread thrombosis (particularly involving platelets) and ischemia leading to organ failure within minutes of engraftment. Recent research advances may hold promise for stopping or ameliorating the antibody mediated HAR. The use of soluble carbohydrate inhibitors to block the recognition of the xenograft by the preformed XNA has shown limited success in animal models, improving graft survival from days to weeks. In addition, use of Decay Accelerating Factor (DAF) in the recipient has effectively stopped the complement-induced damage to the xenograft in some model systems. Currently, transgenic DAF animals are being bred to try to extend the success of intravenous DAF therapy. Other methods being tested include "knockout" pigs missing the gene for the protein responsible for addition of the terminal carbohydrate moiety, and transgenic pigs that contain the genes for human regulator(s) of complement activation (RCA) to prevent complement damage to the organ. While current efforts are focused on preventing HAR, there is growing evidence that a vigorous immune response is still mounted to the non-human organ beyond the HAR response. This Delayed Xenograft Rejection (DXR), or acute vascular rejection, is characterized by mononuclear cell infiltrates, focal infarcts and interstitial hemorrhage with intravascular coagulation. This damage is due to a series of steps involving mononuclear and endothelial cell activation, cytokine expression and platelet and fibrin deposition, leading to xeno-organ rejection within a few days. While there are new, exciting results that will allow xenografts to survive longer, much is still unknown about the immune response to organs from non-human species. Another major concern in xenotransplantation is the transmission of infectious organisms. Transmission of pathogens, such as swine influenza, from animal reservoirs to humans is well documented in settings other than transplantation. Evolutionary adaptation of pathogenic organisms to a wider host range is also well documented. When infectious agents are transmitted from natural hosts to new species, unpredictable changes in the pathogenic potential of these infectious organisms can result. This inter-species infectivity is a problem for xenotransplantation. The infectious disease research that could be supported by this PA is intended to increase our knowledge of and our ability to characterize the infectious organisms and processes involved in xenotransplantation. This would include the use of modern molecular biological techniques to develop new diagnostic methods to detect potential pathogens before animal organs or tissues are transplanted. Research Objectives and Scope The objectives of the research to be supported under this PA are to: delineate the mechanisms and pathology of the delayed xenograft response to antigens found on the surface of non-human organs, tissues or cells that might be used for transplantation into humans; develop new specific and rapid diagnostic tests to identify potential pathogenic organisms; and quantify the risk of xenogeneic infection. 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. These examples are not meant to be inclusive, but rather illustrative of areas that require further investigation. Investigators are encouraged to develop novel approaches to identify and characterize the human immune response to non-human organs or tissues. o Identification of xenoantigens which are immunogenic, such as Major Histocompatibility Complex (MHC) antigens, Minor Histocompatibility Complex (MiHC) antigens, and other cell surface molecules; o Definition of the modes of interaction between xenoantigens and recipient MHC; o Assessment of the risk of transmission of Xenozoonosis (xeno-infectious disease) in immunocompromised hosts; o Development of new diagnostic methods to detect xenozoonoses before they become frank infections; o Studies involving genetic manipulation of the donor animal to either render it less immunogenic or more resistant to the host immune response; o Elucidation of the inflammatory events in delayed xenograft rejection; o Studies of the role of adhesion molecules on the host cell types; e.g. macrophages, NK cells and endothelial cells; o Studies in animal models of in vivo safety and efficacy of antimicrobial therapeutics in immunocompetent and immunocompromised hosts compared with the in vitro sensitivity of the organisms; and o Development of model systems to study the impact of viral mutants, alterations in pathogenicity, infectivity and transmissibility of xeno-infectious organisms in immunocompromised hosts. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification are provided that inclusion is inappropriate with respect to the health of the subjects of the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research", which have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994. 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. Applications kits are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: ASKNIH@odrockm1.od.nih.gov. 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 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 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 (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 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 Written and telephone inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Inquiries regarding programmatic issues may be directed to: Stephen M. Rose, Ph.D. Chief, Genetics and Transplantation Branch Division of Allergy, Immunology and Transplantation National Institute of Allergy and Infectious Diseases Solar Building, Room 4A14 6003 Executive Blvd. Bethesda, MD 20892-7640 Telephone: (301) 496-5598 FAX: (301) 402-2571 EMAIL: sr8j@nih.gov Judith Massicot-Fisher, Ph.D. Heart Failure SRG Leader Division of Heart and Vascular Diseases National Heart, Lung and Blood Institute 6701 Rockledge Drive MSC 7940 Bethesda, MD. 20892-7940 Telephone: (301) 435-0504 Fax: (301) 480-1454 EMAIL: jm294z@nih.gov Joan T. Harmon, Ph.D. Chief, Diabetes Research Section, Division of Diabetes, Endocrinology and Metabolic Diseases National Institute of Diabetes and Digestive and Kidney Diseases Natcher Building, Room 5An-18G Bethesda, MD 20892-6600 Telephone: (301) 594-8813 FAX: (301) 480-3503 Email: harmonj@ep.niddk.nih.gov Direct inquiries regarding fiscal matters to: Laura Eisenman Grants Management Branch Division of Extramural Activities National Institute of Allergy and Infectious Diseases Solar Building, Room 4B23 6003 Executive Blvd. Bethesda, MD 20892-7610 Telephone: (301) 496-7075 Fax: (301) 480-3780 Email: le55d@nih.gov William W. Darby Heart Section Grants Management Officer Grants Operations Branch National Heart, Lung and Blood Institute 6701 Rockledge Drive Room 7128, MSC 7926 Bethesda, MD 20892-7926 Telephone: (301) 435-0177 Fax: (301) 435-3310 EMAIL: William_Darby@nih.gov Linda Stecklein Grants Management Specialist Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases Natcher Building, Room 6As-49J National Institutes of Health Bethesda, MD 20892-6600 Telephone: (301) 594-8847 FAX: (301)480-3504 Email: steckleinl@ep.niddk.nih.gov AUTHORITY AND REGULATIONS This program is supported under authorization of the Public Health Service Act, Sec. 301(c), Public Law 78-410, as amended. The Catalogue of Federal Domestic Assistance Citations are No. 93.855 - Immunology, Allergy, and Transplantation Research, No. 93.848 - Diabetes, Endocrinology and Metabolic Diseases, No. 93.849 - Kidney, Urologic and Hematologic Diseases, and No. 93.837 - Heart and Vascular Diseases Research. Awards will be administered under PHS grants policies and Federal Regulations 24 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 PHS 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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