Full Text PA-95-065 IMMUNOBIOLOGY OF AIDS LYMPHOMAS NIH GUIDE, Volume 24, Number 19, May 26, 1995 PA NUMBER: PA-95-065 P.T. 34 Keywords: AIDS Cancer/Carcinogenesis Immunology National Cancer Institute PURPOSE The intent of this program announcement is to stimulate research on immunologic mechanisms involved in the development of lymphomas in AIDS patients. Because AIDS patients are living longer, the development of lymphomas is becoming a more important clinical problem. Specifically, this program announcement is intended to encourage development and testing of hypotheses about the mechanisms of lymphomagenesis in the unique immune environment induced by HIV infection. This environment is characterized by defects in immune regulation, loss of specific immune cell subsets, presence of abnormal cytokine levels, changes in the architecture of germinal centers and other lymphoid tissues and an apparent loss of immune surveillance. Any or all of these factors may play a role in the high incidence and distinctive characteristics of AIDS-associated lymphomas. The dysregulation may lead to an increase in the rate of generation of transformed lymphocytes and/or to enhanced capacity of these cells to escape surveillance and cause disease. Before effective prevention strategies or therapies can be designed, it is necessary to understand the basic mechanism of lymphomagenesis in AIDS. 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 PA, Immunobiology of AIDS Lymphomas, is related to the priority area of cancer. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238). ELIGIBILITY REQUIREMENTS Applications may be submitted by foreign and 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. Foreign institutions are not eligible for First Independent Research Support and Transition Awards (R29). Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. MECHANISM OF SUPPORT Grants will be awarded as investigator-initiated research project grants (R01) and FIRST (R29) awards. Applications for FIRST Awards and R01s from new investigators are particularly encouraged. RESEARCH OBJECTIVES The incidence of non-Hodgkin's lymphoma (NHL) has increased steadily during the past decade with the most dramatic increase in AIDS-associated B-cell lymphomas. Yet, during the same decade, tremendous progress was made in elucidating mechanisms of B and T lymphocyte regulation in both normal and immunodeficient patients. Emphasis was initially focused on elucidating the cellular and molecular mechanisms that govern the function of the immune system in normal individuals. Comparisons were then made between immune mechanisms in non-immunodeficient and immunodeficient individuals. It became obvious that deficiencies in the functioning components of the immune system, e.g., B or T cells, could readily account for the lack of resistance to infectious diseases in immunodeficient animals and patients. But no such explanation is readily available to explain the etiology of AIDS-associated lymphomas. Studies have shown that similar immune abnormalities exist among patients with congenital and iatrogenic immunodeficiencies and patients with AIDS. For example, low numbers of CD4+ T-cells can be found in the peripheral circulation of all three groups of patients. Similarly, abnormal cytokine levels are detected in both non-AIDS and AIDS patients. One such example is the high levels of interleukin-6 (IL-6) detected in the common variable immunodeficiency (CVI) syndrome and AIDS. This apparently reflects lack of normal B cell function in both groups of patients. However, further studies have shown distinct differences between AIDS and other immunodeficiencies. For example, Epstein-Barr Virus (EBV) was reported to induce essentially all of the B lymphomas in post-transplant recipients but has a lesser role in AIDS-associated lymphomas. Additional studies demonstrated the lack of a direct role for HIV and other viruses in inducing AIDS lymphomagenesis, further emphasizing the unique features of AIDS lymphomas. Other studies support the uniqueness of the AIDS immunodeficiency. For example, a recent report demonstrated a severe disruption of germinal center architecture located within lymph nodes of AIDS patients. Particularly noticeable was an apparent loss of follicular dendritic cell function in these germinal centers, with subsequent loss of immunoregulatory mechanisms controlling B lymphocyte immunobiology. This finding may help to explain a unique feature of AIDS lymphomas in that they are detected at extranodal sites. It is apparent that AIDS patients share similar immune abnormalities with other immunodeficient patients. Yet, as studies have shown, there are immune abnormalities that are unique only to the AIDS patient and contribute to AIDS-associated lymphomas. The goal of this Program Announcement is to encourage research on immune abnormalities and dysfunctions that either contribute to the development or prevent immune control of AIDS-associated B-cell lymphomas. The recent advancements in the understanding of immune regulation in immunodeficient individuals has presented the scientific community with an opportunity to delineate the mechanisms leading to the development of lymphomas in AIDS patients. 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 is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This new policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43) and supersedes and strengthens the previous policies (Concerning the inclusion of Women in Study Populations, and Concerning the Inclusion of Minorities in Study Populations), which have been effect since 1990. The new policy contains some provisions that are substantially different from the 1990 policies. 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 reprinted in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994. Investigators also may obtain copies of the policy from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 9/91) and will be accepted at the standard application deadlines as indicated in the application kit. Application kits are available at most institutional offices of sponsored research and may be obtained from the Office of Grants Information, Division of Research Grants, National Institutes of Health, 6701 Rockledge Drive, Room 3032, MSC 7762, Bethesda, MD 20892-7762, telephone 301/710-0267. The title and number of the program announcement must be typed in Section 2a on the face page of the application. The completed original application and five legible copies 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 (for express/courier service) REVIEW CONSIDERATIONS Applications will be assigned on the basis of established Public Health Service referral guidelines. 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. Following scientific-technical review, the applications will receive a second-level review by an appropriate National Advisory Council or Board. Review Criteria o scientific, technical, or medical significance and originality of proposed research; o appropriateness and adequacy of the experimental approach and methodology proposed to carry out the research; o qualifications and research experience of the Principal Investigator and staff, particularly, but not exclusively, in the area of the proposed research; o availability of the resources necessary to perform the research; o appropriateness of the proposed budget and duration in relation to the proposed research; The initial review group will also examine 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 approved applications. The following will be considered in making funding decisions: Quality of the proposed project as determined by peer review, availability of funds, and program priority. INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: John F. Finerty, Ph.D. Division of Cancer Biology, Diagnosis, and Centers National Cancer Institute Executive Plaza North, Room 501 Bethesda, MD 20892-7381 Telephone: (301) 496-7815 FAX: (301) 496-7815 Email: fin@nih.gov Direct inquiries regarding fiscal matters to: Ms. Sara Stone Grants Management Branch National Cancer Institute Executive Plaza South, Room 243 Bethesda, MD 20892 Telephone: (301) 4976-7800 x266 Email: Stones@GAB.NCI.NIH.gov AUTHORITY AND REGULATIONS This program is described in the catalog of Federal Domestic Assistance No. 93.396. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency 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 routing 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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