Full Text PA-95-065


NIH GUIDE, Volume 24, Number 19, May 26, 1995

PA NUMBER:  PA-95-065

P.T. 34


National Cancer Institute


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


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


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.


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.


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.


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,

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.


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:

6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)


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


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 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


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


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