Full Text PA-96-051
NIH GUIDE, Volume 25, Number 15, May 10, 1996
PA NUMBER:  PA-96-051
P.T. 34

  Immune System Disorders 

National Institute of Allergy and Infectious Diseases
National Institute of Neurological Disorders and Stroke
National Institute of Arthritis and Musculoskeletal and Skin Diseases
The National Institute of Allergy and Infectious Diseases gives
special consideration for funding to scientifically meritorious
applications in response to Program Announcements.  Program
Announcements identify areas of ongoing research emphasis for the
The National Institute of Allergy and Infectious Diseases (NIAID),
National Institute of Neurological Disorders and Stroke (NINDS) and
National Institute of Arthritis and Musculoskeletal and Skin Diseases
(NIAMS) invite applications for basic and preclinical studies to
increase knowledge of the role of microbes in the development and
regulation of chronic pathologic immune responses, including
autoimmune diseases, and to identify the genetic factors that
increase or decrease the susceptibility to pathogen-induced immune
disease.  Exploitation of animal models of microbe-induced autoimmune
disease to molecularly dissect the etiology and pathogenesis of
autoimmune disease would be relevant.  The knowledge developed
through research into the mechanisms by which microbes break
tolerance to self antigens should provide information about the
underlying basis of autoimmunity.
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), Role of Microbes in Autoimmune and Immune-mediated
Diseases, is related to the priority area of diabetes and chronic
disabling diseases.  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 20402-0325 (telephone 202-512-1800).
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.
Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as Principal Investigators.
Foreign institutions are not eligible for the First Independent
Research Support and Transition (FIRST) (R29) award.
Traditional research project grant (R01), FIRST (R29), and small
research grants (R03) may be submitted in response to this program
announcement.  The total requested project period for an application
submitted in response to this PA may not exceed five years; a foreign
application may not request more than three years of support.
NIAID uses R03 grants to support small highly innovative or pilot
projects. Applicants for R03 grants may request up to $50,000 annual
direct costs for a period not to exceed three years.  Funds and time
requested should be appropriate for the research proposed.
Applicants for R03 grants must follow special application guidelines,
SMALL RESEARCH GRANTS -NIAID, which appeared in the NIH Guide for
Grants and Contracts, Vol. 25, No. 9, March 22, 1996, and are
available from the NIAID program staff listed under INQUIRIES.
NINDS and NIAMS do not utilize the R03 mechanism.
Infectious agents and/or their products have been implicated in the
pathogenesis of autoimmune and chronic inflammatory diseases.
Reiter's syndrome and Lyme disease are chronic immune-mediated
inflammatory diseases that are clearly induced by infectious agents.
Infection with Campylobacter jejuni is a common antecedent of the
Guillain-Barre syndrome.  A workshop recently convened by the NIAID
on the Role of Infectious Agents in the Development of Autoimmunity
highlighted this area as important for advancing our understanding of
the pathogenesis of autoimmune disease.  An association of rheumatoid
arthritis with various organisms, including mycoplasma, Epstein-Barr
virus, parvovirus, and rubella, has been suggested, but not
convincingly proven.  Insulin dependent diabetes mellitus (IDDM), a
metabolic disease caused by immune destruction of the pancreatic beta
cells, has also been associated epidemiologically with various
infectious agents, including rubella and Coxsackie virus.  Recently,
cross reactivity of T cell clones to both Coxsackie protein and
glutamic decarboxylase (GAD65), a pancreatic islet beta cell protein
and IDDM-associated antigen, has provided molecular evidence for the
association of IDDM with Coxsackie virus (1-2).  In addition, various
viral and bacterial peptides are able to activate myelin basic
protein specific T cell clones, which were isolated from patients
with multiple sclerosis (3). Various mechanisms by which pathogens
could induce autoimmune or immune-mediated diseases have been
suggested.  The organism may directly generate an immune response by
its continued presence.  Alternately, the organism may induce an
immune response, possibly by revealing self antigens that are
normally sequestered from the immune system, and this autoreactive
response then becomes self-sustaining.  A role for superantigens,
which can be of viral or bacterial origin, has also been postulated.
Superantigens are products of microbes that activate a large
proportion of the host's T cells by interaction with the MHC and the
variable domain of the beta-chain of their antigen receptors.
Recently, isolation of islet infiltrating lymphocytes from the
pancreata of two patients with newly onset IDDM provided suggestive
evidence that a superantigen may be involved in the origin of this
disease (4).
Many of the immune diseases associated with infection have a genetic
component, suggesting that genetic susceptibility may play a role in
the development of pathologic immune responses to microorganisms.  In
fact, the cross reactivity of T cell clones to Coxsackie protein and
GAD65 was only evident in mice with a diabetes susceptible MHC
background (2).
Animal models also provide evidence that infectious agents may play a
role in either initiating or in protecting the host from the
development of autoimmune disease.  For example, the maintenance of
HLA-B27 transgenic mice in germ-free conditions prevents the
development of the inflammatory disease (5).  However, the NOD mouse
develops diabetes at an increased frequency when kept in a "clean"
facility.  Investigation of the role of pathogens in the development
and regulation of the immune response in autoimmune or chronic
immune-mediated inflammatory diseases may lead to new preventive or
therapeutic strategies for these diseases.
Research Objectives and Scope
This PA is designed to support basic and preclinical research on the
role of pathogens in autoimmune and immune-mediated diseases.
Relevant topics of research include, but are not limited to, the
o  mechanisms by which pathogens initiate, potentiate, or perpetuate
a chronic immune response
o  definition of the genetic susceptibility to chronic immunologic
injury related to pathogens
o  molecular, cellular, immunologic, and biological mechanisms of a
host autoimmune associated response to pathogens or pathogen products
o  exploitation of the known animal models of microbially-induced
autoimmune disease and of the known animal models of autoimmunity for
information on the role of infectious agents in their pathogenesis
o  examination of whether persistence of the pathogen in the host is
necessary to cause disease, or can the pathogen initiate a cascade of
irreversible or reversible immunologic consequences.  What factors
determine the mechanism:  the host, the pathogen, or both?
o  hypothesis-driven investigations to establish the role of
infectious agents in the etiology of various human autoimmune
diseases and to determine the fraction of cases attributable to
infectious agents.
The above examples of research approaches are not meant to be all
inclusive or restrictive.  Investigators are encouraged to develop
their own innovative approaches to achieve the goals of this PA.
It is the policy of the NIH that women and members of minority groups
and their sub-populations 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 in 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 printed 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.
Applicants for Small Research (R03) grants are to follow the
application guidelines in the NIH Guide notice entitled "SMALL
Applicants are strongly encouraged to call program staff early in
project development with any questions regarding the responsiveness
of their proposed project to the goals of this PA.  Applications are
to be submitted on the grant application form PHS 398 (rev. 5/95) and
will be accepted on 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 Grants Information Office, Office of Extramural Outreach and
Information, National Institutes of Health, 6701 Rockledge Drive, MSC
7910, Bethesda, MD 20892-7910, telephone (301)435-0714, email:
Each application must be identified by checking "YES" on line 2 of
the face page, and the number and title of this program announcement
must be typed in section 2.
The completed original and five legible, single-sided copies of the
application must be sent or delivered to:
BETHESDA, MD  20892-7710
BETHESDA, MD  20817-7710 (for express/courier service)
R03 APPLICANTS ONLY:  Direct inquiries regarding review issues and
special instructions for application preparation and mail two copies
of the R03 application and all five sets of any appendices to:
Stanley Oakes, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4C06
6003 Executive Boulevard
Bethesda, MD  20892-7610
Telephone:  (301) 496-7042
FAX:  (301) 402-2638
Email:  stanley_oaks@nih.gov
FIRST (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
Applicants from institutions that have a General Clinical Research
Center (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
Applicants for all Small Research (R03) grants must see the REVIEW
Applications will be assigned on the basis of established PHS
referral guidelines.  Applications will be reviewed for scientific
and technical merit 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 about 50 percent of applications under review, will be
discussed, assigned a priority score, and receive a second level
review by the appropriate national advisory council.
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;
o  adequacy of plans to include both genders and minorities and their
subgroups as appropriate for the scientific goals of the 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. Concerns expressed by the initial review group
about any of these factors may influence the recommendation of the
National Advisory Allergy and Infectious Diseases Council or the
advisory council for NIAMS or NINDS.
The following will be considered when making funding decisions:
quality of the proposed project as determined by peer review, program
balance among research areas of the program announcement,
availability of funds.
Written and telephone inquiries concerning this PA are encouraged.
The opportunity to clarify any issues or questions from potential
applicants is welcome.
Direct inquiries regarding programmatic issues to:
Elaine Collier, M.D.
Division of Allergy, Immunology and Transplantation
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4A20
6003 Executive Boulevard - MSC 7640
Bethesda, MD  20892-7640
Telephone: (301) 496-7104
FAX:  (301) 402-2571
Email:  ec5x@nih.gov
A. P. Kerza-Kwiatecki, Ph. D.
Division of Demyelinating, Atrophic, and Dementing Disorders
National Institute of Neurological Disorders and Stroke
Federal Building, Room 804
7550 Wisconsin Avenue - MSC 9150
Bethesda, MD  20892-9150
Telephone:  (301) 496-1431
FAX:  (301)402-2060
Email:  ak45w@nih.gov
Susana Serrate-Sztein, M.D.
Arthritis Branch
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Natcher Building, Room 5AS37G
Telephone:  (301) 594-5032
FAX:  (301) 480-4543
Email:  szteins@ep.niams.nih.gov
Direct inquiries regarding fiscal matters to:
Mrs. Pamela Fleming
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4B30
Executive Boulevard - MSC 7610
Bethesda, MD  20892-7610
Telephone:  (301) 496-7075
FAX:  (301) 480-3780
Email:  pf49e@nih.gov
Ms. Dianna Jessee
Division of Extramural Affairs
National Institute of Neurological Disorders and Stroke
Federal Building, Room 1004
7550 Wisconsin Avenue - MSC 9190
Bethesda, MD  20892-9190
Telephone:  (301) 496-9231
FAX:  (301) 402-0219
Email:  dj35j@nih.gov
Ms. Carol Fitzpatrick
Grants Management Branch
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Natcher Building, Room 5AS43K
Telephone:  (301) 594-3506
FAX:  (301) 480-4543
Email:  fitzpatric@ep.niams.nih.gov
The program is described in the Catalog of Federal Domestic
Assistance, No. 93.855 - Immunology, Allergy and Transplantation
Research, No. 93.853 - Clinical Research of Neurological Disorders
and Stroke, and No 93.846 - Arthritis, Musculoskeletal and Skin
Diseases Research.  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 Part 74.
This program is not subject to the intergovernmental review
requirements of Executive Order 12372 or Health Systems Agency
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.
1.  Atkinson, MA, Bowman, MA, Campbell, L, Darrow, BL, Kaufman, DL,
and MacLaren, NK.  Cellular Immunity to a Determinant Common to
Glutamate Decarboxylase and Coxsackie Virus in Insulin-dependent
Diabetes. Journal of Clinical Investigation 94:2125-2129, 1994.
2.  Tian, J, Lehrmann, PV, and Kaufman, DL.  T Cell Cross-reactivity
between Coxsackie virus and Glutamate Decarboxylase is Associated
with a Murine Diabetes Susceptibility Allele.  Journal of
Experimental Medicine 180: 1979-1984, 1994.
3.  Wucherpfennig, Kai W., and Strominger, Jack L.  Molecular mimicry
in T cell-mediated autoimmunity: viral peptides activate human T cell
clones specific for myelin basic protein.  Cell 80:695-705, 1995.
4.  Conrad, B, Weidmann, E, Trucco, G, Rudert, WA, Behboo, R,
Ricordi, C, Rodriquez-Rilo, H, Finegold, D, and Trucco, M.  Evidence
for superantigen involvement in insulin-dependent diabetes mellitus
aetiology.  Nature 371: 351-355, 1994.
5.  Taurog, JD, Richardson, JA, Croft, JT, Simmons, WA, Zhou, M,
Fernandez-Sueiro, JL, Balish, E, and Hammer, RE.  The Germfree State
Prevents Development of Gut and Joint Inflammatory Disease in HLA-B27
Transgenic Rats. Journal of Experimental Medicine 180:2359-2364,

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