IMMUNOPATHOGENESIS OF TYPE 1 DIABETES MELLITUS

NIH Guide, Volume 26, Number 38, November 21, 1997

RFA:  DK-98-010

P.T.

National Institute of Allergy and Infectious Disease
National Institute of Child Health and Human Development
National Institute of Diabetes and Digestive and Kidney Diseases

Letter of Intent Receipt Date:  February 19, 1998
Application Receipt Date:  March 19, 1998

PURPOSE

The National Institute of Allergy and Infectious Diseases (NIAID), National
Institute of Child Health and Human Development (NICHD), and the National
Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) invite
investigator-initiated research grant applications to elucidate the
immunopathogenesis of type 1 diabetes. Specifically, this Request for
Applications (RFA) focuses on basic research into the role of: viral and
environmental factors, the major histocompatibility complex (MHC) in
susceptibility to and protection from disease, B cells and autoantibodies in
disease pathogenesis, the fetal and neonatal immune response, and interactions
of genetic, immune, and environmental factors in development of disease.  It is
anticipated that results obtained by studies supported by this RFA will enhance
understanding of basic mechanisms and the application of this knowledge to the
development of novel approaches to immunomodulation and immunoprevention.

This RFA is intended to stimulate the application of advances in immunology,
virology, cell biology, molecular biology, and endocrinology to the study of the
pathogenesis of type 1 diabetes mellitus.  Participation of virologists and
infectious disease experts to focus on type 1 diabetes is highly desirable. 
Collaborative efforts linking expertise in these disciplines to expertise in
diabetes are strongly encouraged.  Two-year pilot and feasibility applications
and interactive research projects, which will support the efforts of several
independent investigators, working in a collaborative manner, are available
within this RFA.

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 RFA, Immunopathogenesis of Type 1
Diabetes Mellitus, is related to the priority area of diabetes and chronic
disabling conditions.  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: 202-512-1800).

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.  Racial/ ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as Principal Investigators.

MECHANISM OF SUPPORT

Support of this program will be through the National Institutes of Health (NIH)
Research Project Grant (R01), Interactive Research Project Grant (IRPG), and
Exploratory/Developmental Research Grant (R21) award mechanisms.  Guidelines for
preparing IRPG applications are available from the program official or from the
internet at: http://grants.nih.gov/grants/guide/pa-files/PA-96-001.html.

The R21 awards are to demonstrate feasibility of a concept and to generate
sufficient preliminary data to pursue it through other funding mechanisms.  These
grants are intended to (1) provide initial support for new investigators; (2)
allow exploration of possible innovative new leads or new directions for
established investigators; and (3) stimulate investigators from other areas to
lend their expertise to research within the scope of this solicitation. 
Applicants for the R21 must limit their requests to $100,000 direct costs per
year and are limited to two years.

This RFA is a one-time solicitation.  Future unsolicited competing continuation
applications will compete with all investigator-initiated applications and be
reviewed according to the customary peer review procedures.

Applicants anticipating submitting IRPG applications or applicants requesting
more than $500,000 in direct costs per year for any year should consult with the
NIAID Program Official listed under "INQUIRIES" at an early opportunity. 
Applicants for R01 mechanism must receive permission from the NIAID prior to the
submission of an application requesting more than $500,000 in direct costs per
year for any year of the proposed study.  NIAID staff will coordinate
consideration and acceptance of such large applications by the staff of the
appropriate Institute.

The total requested project period for an application submitted in response to
this RFA may not exceed three years.  Budget escalations in future years should
be limited to 3% of recurring costs.  The anticipated award date is September 30,
1998.  Responsibility for the planning, direction, and execution of the proposed
project will be solely that of the applicant.  Awards will be administered under
Public Health Service (PHS) grants policy as stated in the PHS Grants Policy
Statement.

FUNDS AVAILABLE

For FY 1998, $4 million will be committed to fund applications submitted in
response to this RFA.  It is anticipated that 16 to 18 awards will be made. 
However, this funding level is dependent upon the receipt of a sufficient number
of applications of high scientific merit.  The award of grants pursuant to this
RFA is also contingent upon the availability of funds for this purpose.  Funding
beyond the first and subsequent years of the grant will be contingent upon
satisfactory progress during the preceding years and availability of funds.

RESEARCH OBJECTIVES

Background

Type 1 diabetes is an autoimmune disease in which cytotoxic T cells destroy the
insulin producing beta cells of the pancreas leading to the development of
hyperglycemia.  The incidence of this disease appears to be increasing worldwide. 
Although the disease may occur at any age, onset peaks prior to 20 years of age. 
In some populations, about one percent of all newborns will develop type 1
diabetes during their lifetime.

On September 4 and 5, 1997, the NIH sponsored a conference entitled "Diabetes
Mellitus: Challenges and Opportunities."  This conference highlighted research
opportunities in several areas.  Some of the most promising areas included: 1)
a need for high quality, insightful studies into the role of environmental and
infectious agents, particularly viruses, in susceptibility to and pathogenesis
of type 1 diabetes with recruitment of experts in virology and infectious
diseases to focus on this area; 2) understanding of the mechanisms by which the
MHC loci lead to susceptibility to or protection from diabetes; 3) an
understanding of the role of B cells and autoantibodies in the process of T cell
destruction of the beta cells; and 4) increased understanding of the fetal and
neonatal immune response in the pathogenesis of type 1 diabetes.  Further
understanding in these areas could lead to the development of new
immunomodulatory and "vaccination" strategies for prevention and treatment. 
"Vaccination" for prevention and treatment of diabetes could include tolerance
induction to inciting antigens, whether viral, environmental, or endogenous,
stimulation of protective immunoregulatory pathways, or down-regulation of self-
reactive immune responses.

Scope and Objectives

The objective of this RFA is to encourage research that will offer an improved
understanding of the basic mechanism(s) involved in type 1 diabetes and will lead
to the development of novel approaches to immunomodulation and immunoprevention. 
The scope of this RFA includes the following areas of emphasis:

It has been suggested that exposure to environmental and infectious agents are
important in the development of type 1 diabetes.  The lack of complete
concordance between monozygotic twins for the development of type 1 diabetes
suggests that non-genetic factors may be involved.  Various infectious agents,
including Coxsackie virus, rubella, enterovirus, and recently, a retroviral
superantigen have been postulated to trigger type 1 diabetes.  Other
environmental agents, including milk protein, have also been suggested to
influence the development of disease.  It is essential to initiate rigorous
studies of environmental risks, both infectious and non-infectious, and the
mechanisms by which these agents may alter the immune response and lead to type
1 diabetes.  There is a need to bring the expertise of virologists and other
infectious disease specialists to bear on this important question.  The role of
environmental agents in determining the immune response in genetically
susceptible individuals needs to be investigated.  The possibility that certain
environmental or infectious agents may induce a protective response has not been
fully explored.  Molecular mimicry is one possible mechanism by which infectious
and environmental agents may influence the development of an autoimmune response;
however, other mechanisms also need further exploration.  A greater understanding
of the role of organisms in the development of type 1 diabetes may lead to new
strategies to prevent this disease, including early protective vaccination.

The Major Histocompatibility Complex (MHC) is the genetic region with the
strongest association to type 1 diabetes. These genes are found in the HLA-D
region in humans and in the I region in mice.  There are both susceptibility and
protective loci within this region of the genome. However, the mechanisms by
which this genetic locus affect the immune response is not clear.  The MHC region
codes for the class I and class II molecules on the surface of cells.  These
molecules are involved in the presentation of antigen to T cells, leading to
their activation.  In addition to their role in antigen presentation, peptides
from the MHC molecules have also been shown to be presented themselves by other
MHC molecules.  Susceptibility to type 1 diabetes is associated with the DR3,
DR4, DQ8, and DQ3.2 regions.  A strong protective effect is seen with the
presence of DR2 haplotype containing DQB1*0602.  The mechanism of this protection
is not known, but one hypothesis that needs further investigation is that this
locus competes with susceptibility loci for binding of peptides.  Several factors
may be important in the MHC, including the density of MHC molecules, the affinity
of MHC molecules, and the particular combination of MHC molecules.  Single amino
acid changes in either the MHC locus or the peptide may alter which pathway is
activated in the T cell.  The interaction of the products of other genetic loci
with MHC molecules is also unclear.  Studies of the peptide binding
characteristics of these protective and susceptibility loci may provide insight
into important antigenic peptides and antigens critical for protection from and
development of type 1 diabetes.  An understanding of the interactions of the
antigen-MHC-T cell receptor complex in type 1 diabetes is critical to the
development of innovative procedures to intervene in a highly specific manner to
prevent the activation of beta cell specific cytotoxic T cells.  Studies to
address the mechanisms of this and other genetic loci in the autoimmune response
are sought.

One of the earliest markers for the potential development of type 1 diabetes in
relatives of individuals with the disease is the presence of various
autoantibodies, including those to glutamic acid decarboxylase (GAD), insulin,
heat shock protein, and several other islet cell components.  Presently, the role
of these autoantibodies in the pathogenesis of type 1 diabetes is unclear.
Recently, the importance of the interaction and cooperation of B cells with T
cells in the development of the immune response has been emphasized.  However,
the role of B cells in the pathogenesis of type 1 diabetes is controversial. 
Further understanding of the role which B cells and autoantibodies play in the
pathogenesis of islet cell destruction could lead to new preventive strategies
or improved detection methods to quantitate progression of type 1 diabetes.

Type 1 diabetes typically has its onset in childhood with a major peak in
incidence before the age of five years and another at puberty.  The incidence of
this disease appears to be increasing particularly in the youngest age group. 
The reasons for this increase are unknown.  One possibility is that the decrease
in infectious diseases in young children with increased public health measures
may prevent development of infection with protective organisms.  The role of the
fetal, neonatal, or childhood immune response in the susceptibility to or
protection from the development of type 1 diabetes is unclear.  A recent study
showed an increased frequency of enteroviral antibodies in the serum of mothers
at the time of birth of infants who later developed type 1 diabetes.  Thus viral
or other influences in the fetal or neonatal state may affect the development of
the autoimmune response later in life.  In addition, increased understanding of
the fetal and neonatal immune response is needed to facilitate development of
novel "vaccination" strategies for the prevention of diabetes.

Responses to this RFA are not limited to the approaches identified.  Innovative
approaches to understand these areas of emphasis are particularly sought as are
studies to define the interaction of genetic, environmental and immune factors
in the pathogenesis of this disease. Other areas of research interest responsive
to this RFA include, but are not limited to:

o  Identification of beta cell antigens and/or epitopes that can be used to
induce tolerance in type 1 diabetes.

o  Identification of the costimulatory molecules involved in the autoimmune
response in type 1 diabetes. Development of agonists and antagonists to modulate
this activity and block or mitigate the autoimmune attack on the beta cell.

o  Identification of cytokines or cytokine inhibitors that can divert a Th1 to
a Th2 response in type 1 diabetes and the role of such molecules in disease
prevention and treatment.

o  Identification of methods to reduce the levels of expression of beta cell
target antigens or impair their processing, binding and presentation in order to
prevent disease.

o  Identification of cellular and serum markers that can be used to track the
activity of the autoimmune attack on beta cells in order to assess the utility
of various strategies of immunomodulation.

o  Identification of the mechanisms by which autoreactive T cells against beta
cell antigens are regulated; development of methods to restore normal regulation
of these autoreactive T cells.

o  Elucidation of the mechanisms of beta cell antigen binding and presentation
by Class II HLA molecules.

o  Identification of the molecular basis for the protective nature of HLA
DQA1*0102 and DQB1*0602 molecules.

o  Isolation, crystallization and sequencing of HLA Class II gene products that
are associated with either increased susceptibility to type 1 diabetes or with
protection from type 1 diabetes.

o  Elucidation of the mechanism of epitope spreading and ascertaining its
association with progression of autoimmune islet cell destruction.

o  Development of animal models of type 1 diabetes which closely parallel the
human disease.

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
sub-populations must be included in all NIH supported biomedical and behavioral
research projects involving human subjects, unless a clear and compelling
rational and justification is provided that inclusion is inappropriate with
respect to the health of the subjects or 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 in the NIH GUIDE FOR GRANTS AND CONTRACTS, Volume 23,
Number 11, March 18, 1994.

Investigators may also obtain copies from these sources or from the program staff
or contact person listed under INQUIRES.  Program staff may also provide
additional relevant information concerning the policy.

LETTER OF INTENT

Prospective applicants are asked to submit, by February 18, 1998, a letter of
intent that includes a descriptive title of the proposed research; the name,
address, and telephone number of the Principal Investigator; the identities of
other key personnel and participating institutions; and the number and title of
this RFA.  Although a letter of intent is not required, is not binding, does not
commit the sender to submit an application, and does not enter into the review
of a subsequent application, the information that it contains allows NIAID staff
to estimate the potential review workload and avoid conflict of interest in the
review.  The letter of intent is to be sent to Dr. Kevin Callahan at the
addresses listed under INQUIRIES.

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 5/95) is to be used in applying
for these grants.  These forms 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 301/435-0714, email: 
ASKNIH@od.nih.gov.

Applications must be received by March 19, 1998.  Applications not received as
a single package on the receipt date or not conforming to the instructions
contained in the PHS 398 (rev. 5/95) Application Kit will be judged non-
responsive and will be returned to the applicant.  For purposes of identification
and processing, item 2a on the face page of the application must be marked "YES"
and the RFA number and RFA title must be typed on line 2 of the face page.  The
RFA label available in the PHS 398 (rev. 5/95) application form must be affixed
to the bottom of the face page of the application.  Failure to use this label
could result in delayed processing of the application such that it may not reach
the review committee in time for review.

If a collaboration of individual investigators is planned, it is necessary to
identify one of the investigators as the group coordinator and to cite this
individual in all applications on page 2 of the form PHS 398 (rev. 5/95). 
Applicants who are have entered into a collaboration may submit the applications
individually with a cover letter noting their involvement and listing the other
members of the collaboration.  These applications should all include the
DESCRIPTION OF INTERACTIVE RESEARCH ACTIVITIES.

If the application submitted in response to this RFA is substantially similar to
a grant application already submitted to the NIH for review, but that has not yet
been reviewed, the applicant will be asked to withdraw either the pending
application or the new one. Simultaneous submission of identical applications
will not be allowed, nor will essentially identical applications be reviewed by
different review committees. Therefore, an application that is essentially
identical to one that has already been reviewed cannot be submitted in response
to this RFA.  This does not preclude the submission of substantial revisions of
applications already reviewed, but such applications must include an introduction
addressing the previous critique.

Submit a signed, typewritten original of the application, including the
Checklist, plus three signed, exact, single-sided photocopies and one copy of the
appendix material, in one package to:

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040-MSC 7710
BETHESDA, MD 20892-7710
BETHESDA, MD 20817 (for express/courier service)

At time of submission, two additional exact copies of the application and all
five sets of any appendix material must be sent to Dr. Kevin Callahan at the
address listed under INQUIRIES.

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
GCRC as a resource for conducting the proposed research.  If so, a letter of
agreement from either the GCRC program director or principal investigator should
be included with the application.

REVIEW CONSIDERATIONS

Applications that are complete and responsive to the RFA will be evaluated for
scientific and technical merit by an appropriate peer review group convened in
accordance with NIH peer review procedures.  As part of the initial merit review,
all applications will receive a written critique and undergo a process whereby
only those applications deemed to have the highest scientific merit will be
discussed, assigned a priority score, and receive a second level review by the
National Advisory Council of the assigned Institutes.

Review Criteria

The five criteria to be used in the evaluation of grant applications are listed
below.  To put those criteria in context, the following information is contained
in instructions to the peer reviewers.

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 comment on the following aspects of the application in their
written critiques 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.  For foreign applications, availability of special opportunities for
furthering research programs through the use of unusual talent resources,
populations, or environmental conditions in other countries which are not readily
available in the United States or which provide augmentation of existing United
States resources.

R21 applications will have the additional review criteria:

o  Potential for novel and innovative approaches that clearly require additional
preliminary data for their value to be established.

IRPG applications will have these additional review criteria:

o  Each component R01 of the IRPG will be reviewed as above for its independent
scientific merit.

o  The reviewers will assess the intended IRPG interactions, including the
effectiveness and feasibility of the proposed IRPG group interactions, whether
or not they enhance the prospects for reaching the stated objectives of the
group, and the extent of synergy among the various projects.

AWARD CRITERIA

The anticipated date of award is September 30, 1998. Funding decisions will be
made on the basis of scientific and technical merit as determined by peer review,
program balance, and the availability of funds.

INQUIRIES

Written, telephone or email inquiries concerning this RFA 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.
Autoimmunity Section
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4A20
Bethesda, MD  20892-7640
Telephone:  (301) 496-7104
FAX:  (301) 402-2571
Email:  ec5x@nih.gov

Gilman D. Grave, M.D.
Center for Research for Mothers and Children
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 4B11 - MSC 7510
Bethesda, MD  20892-7510
Telephone:  (301) 496-5593
FAX:  (301) 480-9791
Email:  GRAVEG@HD01.NICHD.NIH.GOV

Joan T. Harmon, Ph.D.
Diabetes Research Section
National Institute of Diabetes and Digestive and Kidney Disease
45 Center Drive, Room 5AN-18G, MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8808
FAX:  (301) 480-3503
Email:  Joan_Harmon@nih.gov

Direct inquiries regarding review issues and special instructions for application
preparation; one copy of the letter of intent, and mail two copies of the
application and all five sets of the appendices to:

Kevin M. Callahan, Ph.D.
Division of Extramural Affairs
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4C20, MSC 7610
Bethesda, MD  20892-7610
Telephone:  (301) 496 -8424
FAX:  (301) 402-2638
Email:  kc92t@nih.gov

Direct inquiries regarding fiscal and administrative matters to:

Pam Fleming
Division of Extramural Affairs
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4C25, MSC 7610
Bethesda, MD  20892-7610
Telephone:  (301) 402-6580
FAX:  (301) 480-3780
Email:  pf49e@nih.gov

E. Douglas Shawver
Grants Management Branch
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 8A17 - MSC 7510
Bethesda, MD  20892-7510
Telephone:  (301) 496-1303
FAX:  (301) 402-0915
Email:  shawverd@hd01.nih.gov

Nancy C. Dixon
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Disease
45 Center Drive MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8854
FAX:  (301) 480-4237
Email:  dixonn@extra.niddk.nih.gov

SCHEDULE

Letter of Intent Receipt Date:  February 19, 1998
Application Receipt Date:       March 19, 1998
Initial Review:                 June/July 1998
Second Level Review:            September 1998
Anticipated Date of Award:      September 30, 1998

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.855 (Immunology, Allergy, and Transplantation Research), No. 93.847 (Diabetes,
Endocrinology and Metabolism Research), and No. 93.865 (Research for Mothers and
Children).  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 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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