NIAID Plan for Research on Immune Tolerance
PART 3: Detailed Research Plan
Solid organ and cell transplantation provide fertile ground for the evaluation
of strategies to achieve tolerance. Since much of the pre-clinical work
on immune tolerance has focused on kidney and islet transplantation, these
two areas of investigation hold the most promise for moving research into
the clinical setting. NIAID's established leadership role in kidney transplantation
clinical trials and the availability of a cooperative infrastructure for
evaluating tolerogenic approaches provide a compelling rationale for studies
in kidney transplantation. Importantly, this cooperative effort has identified
sensitive early predictors of rejection which can be readily quantified
in peripheral blood and urine. In the case of islet transplantation, engraftment
and one-year graft survival are poor (less than 5% insulin independence
at one year) even with aggressive non-specific immunosuppression. Hence,
there is a clear need to develop new approaches including the induction
of donor-specific tolerance. Furthermore, NIAID currently supports a highly
qualified cadre of investigators whose work is already focused on tolerogenic
approaches relevant to kidney and islet transplantation. Finally, from
an ethical standpoint, the availability of "rescue" therapies (hemodialysis
and insulin therapy) for both kidney and islet transplant recipients will
facilitate clinical evaluation.
KIDNEY TRANSPLANTATION
Kidney Transplantation: Specific Initiatives
- Expansion of research in non-human primate models followed by pilot
clinical trials.
- Expansion of the NIAID Cooperative Clinical Trial in Adult Kidney
Transplantation to conduct multi-center efficacy trials.
- Establishment of a prospective registry of kidney transplant recipients
and a repository of tissue and blood samples.
Kidney Transplantation: Detailed Research Plan
Development and evaluation of tolerogenic approaches in kidney transplantation
will require a phased approach to provide adequate data for the design
of efficacy trials without standard immunosuppression. This plan includes:
(1) non-human primate studies to refine tolerogenic regimens and provide
for longer-term assessements of efficacy alone and in combination with
immunosuppressive therapy; (2) further definition of the mechanisms of
action of these experimental treatments; (3) development of effective
monitoring strategies, including methods to demonstrate the induction
or loss of immune tolerance in humans; (4) pilot clinical trials of safety
and potential efficacy; and (5) multi-center efficacy trials.
Non-Human Primate Studies and Pilot Clinical Trials
The plan focuses on unsolicited and solicited research and involves NIAID
staff working closely with investigators and pharmaceutical and biotechnology
companies to identify promising projects. Two specific projects under
development are outlined below, and additional opportunities in this area
are being pursued.
Research conducted by the Naval Medical Research Institute provides a
foundation for advancing our understanding of immune tolerance in kidney
transplantation. These studies should be expanded to provide the data
necessary for the design of pilot clinical trials and should include:
(1) additional studies of anti-CD40 ligand antibody, alone and in combination
with various single immunosuppressive agents, in monkeys with MHC-mismatched
kidney transplants; (2) evaluation of the effect of administration of
donor bone marrow cells at the time of anti-CD40 ligand antibody treatment
to determine if the presence of donor cells extends the ability to maintain
long-term tolerance; (3) studies of underlying mechanisms and markers
of tolerance in these monkey models; and (4) pilot clinical trials of
safety and potential efficacy. Support will also be important for studies
of second generation agents, such as high affinity anti-CD40 ligand antibody,
to evaluate whether reduced doses of such molecules can induce tolerance
in fully mismatched kidney transplants in a monkey model.
Other studies show promising preliminary results, including a pilot clinical
study of a humanized, non-activating anti-CD3 antibody for reversal of
acute kidney rejection. Such efforts should be expanded for both reversal
of rejection and tolerance induction. Furthermore, additional strategies
are worthy of investigation, including the use of bone marrow or purified
stem cells to deliver tolerogenic signals and gene transfer approaches
for the delivery of immunomodulatory agents.
Expansion of the NIAID Cooperative Clinical Trials in Adult Kidney
Transplantation
The development of tolerogenic treatment strategies will require the
capacity to conduct multi-center clinical trials. The NIAID Cooperative
Clinical Trials network in adult kidney transplantation, established in
1991 and currently composed of 52 participating sites, can provide the
infrastructure necessary to evaluate the safety and efficacy of promising
approaches to achieve and maintain tolerance in kidney transplant recipients.
An expansion of this cooperative research program will provide the resources
necessary to conduct Phase I, II and III clinical trials within the existing
sites and to expand the number of participating sites to ensure an adequate
accrual for all phases of clinical investigation. Based on the results
of studies in adults with respect to safety, toxicity and proof of concept,
clinical trials in pediatric kidney transplant recipients can be initiated.
This expanded clinical research program will be supported by the Human
Immunology Cooperative Study Groups to standardized immune markers of
tolerance induction and maintenance, study mechanisms of action of various
tolerogenic therapies, and develop improved methods to detect and predict
acute and chronic rejection.
Prospective Registry of Kidney Transplant Recipients
Establishment of an NIAID-supported registry and repository will provide
the stable infrastructure necessary to collect recipient and donor samples
and conduct relevant studies of long-term clinical outcomes.
ISLET TRANSPLATATION
Islet transplantation seeks to restore pancreatic beta cell function
by replacing the pancreatic insulin-producing cells destroyed by immune-mediated
injury in type 1 diabetes mellitus. The ultimate goal is to provide a
sufficient number of functioning islets to achieve normal insulin production
and secretion and to prevent the serious renal, neurologic and vascular
complications of this disease. In patients with type 1 diabetes mellitus,
fewer than 5% of those receiving islet transplants in conjunction with
aggressive immunosuppressive therapy remain insulin-independent at one
year. This poor outcome could be the result of recurring autoimmune destruction
or immune rejection. Furthermore, the immunosuppressive agents themselves
are responsible for at least some of this destruction. These sobering
results highlight the importance of developing other approaches to ensure
successful engraftment, survival and normal function. Furthermore, islet
transplantation is an exceptional clinical setting to test tolerance induction
protocols since transplant failure is not life-threatening and patients
can be returned to insulin therapy without detrimental long-term consequences.
In addition, islet transplantation will provide valuable new information
on the ability to induce tolerance in the context of an underlying autoimmune
disease.
Most research in this area is being conducted in rodent models, with
some promising studies in non-human primates, and a small but evolving
effort in human islet transplantation. The immunologic hurdles are considerable
and overcoming them will require additional investments in basic, pre-clinical
and clinical research. The major areas in need of further investigation
include:
- Identification of various transplant sites and modes of islet delivery
to optimize engraftment, short- and long-term survival, and endocrine
function.
- Evaluation of specific treatment regimens including the number of
cells required for initial transplantation, maintenance and retreatment
regimens, as well as pre-treatment strategies.
- Immunological mechanisms of early cell destruction and therapeutic
interventions to prevent such destruction.
- Approaches to improve short- and long-term survival by combining islet
transplantation with promising tolerogenic molecules and reagents.
- The role of disease recurrence (i.e., autoimmune injury) in the destruction
of transplanted islets.
- The development of "super" islets, including genetically engineered
beta cells and tissues, to improve engraftment and function and to escape
autoimmune injury and transplant rejection.
Islet Transplantation: Specific Initiatives
- Research in non-human primate models.
- Establishment of a Cooperative Clinical Trial Network for Human Islet
Transplantation.
- Developmental/exploratory research projects and Small Business Innovative
Research (SBIR) grants.
Islet Transplantation: Detailed Research Plan
Non-Human Primate Studies
The approach to advancing investigations in non-human primate models
of islet transplantation focuses on unsolicited research and involves
NIAID staff working closely with investigators and pharmaceutical and
biotechnology companies to identify promising studies and tolerogenic
approaches. Two specific projects are described below and additional opportunities
will be pursued.
Recently published results by an NIAID grantee highlight the potential
for achieving long-term graft survival using an anti-CD3 immunotoxin molecule
in a monkey model of kidney transplantation. This work is now being extended
to islet transplantation in a newly identified and unique population of
rhesus monkeys with spontaneous diabetes mellitus. Preliminary results
indicate that the immunotoxin-treated animals remain insulin-independent
with none of the usual complications of this disease. Furthermore, reconstitution
of general immune function has been demonstrated. Such non-human primate
studies should be expanded to provide the data necessary to design pilot
clinical trials of safety and potential efficacy.
In addition, the promising results from the Naval Medical Research Institute
study of anti-CD40 ligand antibody for kidney transplantation are being
extended to islet transplantation. Preliminary investigations of the use
of this molecule in baboons have been conducted by the Diabetes Research
Institute at the University of Miami. Results from these early efforts
show that anti-CD40 ligand antibody is able to prevent islet destruction
post-transplant and recurrent autoimmune destruction of the transplanted
cells. Similarly, additional studies of this co-stimulatory blockade approach,
as well as other strategies, merit further investigation in non-human
primates and man. Other approaches include: (1) the use of a humanized,
non-activating anti-CD3 antibody for tolerance induction in non-human
primates; (2) further evaluation of anti-CD40 ligand antibody; and (3)
studies of CTLA4-Ig and anti-B7 antibodies.
NIAID Cooperative Clinical Trials in Islet Transplantation
The small but growing effort to study immune tolerance in human islet
transplantation consists primarily of individual pre-clinical and pilot
clinical studies under industry sponsorship with little NIH involvement.
Advances in this area will require the capacity to design and conduct
standardized protocols at multiple sites. Therefore, the establishment
of a program for cooperative clinical trials in islet transplantation
will provide the infrastructure and the clinical and basic science expertise
necessary for more rigorous and standardized evaluations of safety and
efficacy. This new clinical network will be supported by the Human Immunology
Cooperative Study Groups for investigations of mechanisms of action, improved
methods to detect and predict rejection, as well as standardization of
immune markers of tolerance induction and maintenance.
Developmental/Exploratory Research Projects and Small
Business Innovative Research (SBIR) Grants
Progress in islet transplantation is impeded by both immunologic and
non-immunologic limitations. Two of the most critical obstacles include
procuring sufficient numbers of islets and the immune destruction of transplanted
beta cells.
Research to date has relied on the procurement of islets from cadaveric
donors-a severely limited source of cells suitable for transplantation.
Other largely under-explored beta cell replacement strategies include
beta cells grown in culture to expand the number available for transplantation
and bioengineering strategies encompassing: the production of non-beta
cells transfected with genes and regulatory elements to mimic beta cell
function, and human beta cells engineered to enhance engraftment and/or
prevent rejection. Progress in this area will require research to determine
those functional beta cell components necessary for glucose-regulated
insulin secretion, including the internal beta cell machinery, interactions
among beta cells, and interactions between beta cells and the extracellular
milieu.
Pre-clinical and clinical research in islet transplantation have revealed
an early, primary destruction of transplanted cells by both immune and
non-immune mechanisms which are, to date, largely undefined. One approach
to prevent the immune destruction involves isolation of the transplanted
cells from the immune system and is being pursued by NIAID and the pharmaceutical
and biotechnology industry. There are several methods to achieve isolation,
including: implantation in an immune-privileged site; encapsulation in
an immune protective membrane; and co-transplantation of beta cells with,
for example, transfected myoblasts secreting agents (TNF or Fas-L) to
induce apoptosis of the invading cytotoxic lymphocytes. Exploratory research
in this area merits further development.
Efforts to induce tolerance in autoimmunity have focused primarily on
the oral administration of antigens. Oral administration of both high-and-low
dose antigen results in a phenomenon termed "oral tolerance" in which
the immune response to subsequent systemic administration of antigen is
blocked. Oral tolerance can be induced in animal models and is now being
evaluated in human diseases. However, the encouraging responses in animal
studies have not been duplicated in recent clinical trials of rheumatoid
arthritis and multiple sclerosis. A clinical trial of oral insulin comprises
one limb of the NIH-sponsored Type 1 Diabetes Prevention Trial (DPT-1).
Results of this large clinical trial, which also includes low-dose parenteral
insulin for at-risk nondiabetic relatives of individuals with type 1 diabetes
mellitus, will not be available for several years. However, there are
a number of promising tolerogenic approaches other than oral tolerance
that can now be pursued in immune-mediated diabetes and other autoimmune
diseases. These include: co-stimulatory blockade; anti-cytokine monoclonal
antibodies; hematopoietic stem cell and bone marrow transplantation; and
gene transfer-based therapies for cytokine modulation.
These approaches will require extensive collaborations among basic immunologists
and clinical investigators from many specialties. Therefore, a major thrust
of the research initiatives in this area focuses on the establishment
of cooperative research programs capable of incorporating the basic science
and clinical expertise necessary to accelerate progress.
The rationale for initiating pilot clinical trials is based on multiple
factors. First, several mouse studies have indicated that co-stimulatory
blockade (e.g., anti-CD40 ligand or CTLA4-Ig antibody treatment) can reverse
experimental autoimmune disease. Second, very few non-human primate models
of human autoimmune disease exist and the models that do exist have not
proved useful for pre-clinical evaluation of therapeutic approaches. Finally,
studies in humans are already underway under the sponsorship of several
pharmaceutical and biotechnology companies.
Autoimmune Diseases: Specific Initiatives
- Individual pilot clinical trials of the safety and potential efficacy
of tolerogenic molecules/reagents.
- Establishment of a Cooperative Clinical Trial Group for the study
of immune tolerance in autoimmunity.
Autoimmune Diseases: Detailed Research Plan
Pilot Clinical Trials
Support for pilot clinical trials to evaluate the safety and potential
efficacy of promising tolerogenic approaches will be the initial phase
of development. Investigators are currently developing pilot clinical
studies to delay disease progression for newly diagnosed type 1 diabetics
and in diabetic patients refractory to standard therapy. In addition,
industry and some individual investigators are targeting systemic lupus
erythematosus, rheumatoid arthritis, and multiple sclerosis. Clinical
trials underway include:
Company/
Investigator |
Product |
Disease |
Anergen |
AnervaX
AnergiX |
rheumatoid arthritis
multiple sclerosis |
Biogen |
anti-CD40L |
lupus nephritis
idiopathic
thrombocytopenic purpura |
Bristol-Meyers Squibb |
CTLA4-Ig |
psoriasis |
Jeffrey Bluestone |
anti-CD3 |
type 1 diabetes |
Examples of the research being carried out at present include Biogen's
ongoing work with anti-CD40 ligand antibody for the treatment of Idiopathic
Thrombocytopenia Purpura (ITP) and lupus nephritis. ITP is a T cell-dependent,
antibody-mediated autoimmune disease in which platelets are destroyed.
Two-thirds of ITP patients are cured by splenectomy, but one-third are
refractory to this aggressive treatment and remain chronically at risk
for life-threatening hemorrhage, especially in the central nervous system.
The rationale underlying this therapeutic approach is the ability of anti-CD40
ligand antibody to regulate T cell-dependent antibody production. In addition,
the endpoints for therapeutic response are readily discernable, i.e.,
a rise in platelet counts and decreases in titers of anti-platelet antibodies
and in the number of transfusions required. Research of this type offers
the opportunity to: study mechanisms of disease amelioration; determine
the effects of anti-CD40 ligand antibody on autoantibody production; and
examine the potential application of this therapy for other T cell-dependent,
antibody-mediated autoimmune diseases, such as systemic lupus erythematosus.
Biogen has promising preliminary results from studies of anti-CD40 ligand
antibody in mice with lupus nephritis, also a T cell-dependent, autoantibody-mediated
autoimmune disease. This treatment prevented the onset of disease and,
in mice with advanced lupus nephritis, has produced a dramatic increase
in survival and a decrease in proteinurea. In addition, the treatment
has resulted in a partial reversal of the normally severe glomerular injury
characteristic of this disease. Testing safety and potential efficacy
in humans will be the next step in the development of this molecule and,
if successful, could pave the way for its use to treat and prevent other
complications of this disease, e.g., neurologic, rheumatologic and hematologic.
In other autoimmune diseases, interactions between antigen-presenting
cells and T cells produce inflammatory molecules responsible for tissue,
nerve and organ damage. One promising therapeutic approach involves interrupting
or preventing these interactions. Two products, developed by Anergen Inc.,
are being evaluated in clinical trials of multiple sclerosis and rheumatoid
arthiritis. AnergiX uses specific self-peptides, complexed with soluble
Major Histocompatibility Complex (MHC) class II molecules, to stimulate
disease-specific T cells in the absence of a co-stimulatory signal. As
a result, specific T cells are inactivated and no longer produce inflammatory
molecules. Pilot clinical trials are underway and preliminary results
are promising.
The second product, AnervaX, is based on the same principle, but does
not require knowing the identify of the disease-causing autoantigen. AnervaX
exploits the strong MHC-linkage of many autoimmune diseases by vaccinating
with an immunodominant epitope of the disease-linked MHC molecules to
induce a host-immune response which blocks subsequent antigen presentation
by those molecules to disease-causing autoreactive T cells. As a result,
the T cell is not activated, no inflammatory mediators are produced, and
disease is prevented. Phase II trials for rheumatoid arthritis are underway
and appear promising.
NIAID Cooperative Clinical Trial of Immune Tolerance for Autoimmune
Diseases
The NIAID Cooperative Clinical Tnamerial of Immune Tolerance for Autoimmune
Diseases will design and conduct efficacy studies in type 1 diabetes,
multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus,
with all studies incorporating investigations of underlying mechanisms.
A cooperative approach has many important strengths. The multi-site infrastructure
will ensure that adequate numbers of patients are available for clinical
trials. This is particularly important for the many autoimmune diseases
which afflict only a small proportion of the population. In addition,
such a network promotes the participation of multiple clinical specialties
relevant for autoimmune disease and collaboration among clinical and basic
scientists to further understanding of the underlying immune mechanisms.
A cooperative research program will also enable the participation of multiple
NIH Institutes with responsibility for research on specific autoimmune
diseases and aid in bringing together the clinical investigators supported
by other NIH components and the basic immunology community within NIAID's
portfolio. As noted above, several pharmaceutical and biotechnology companies
and individual investigators are already pursuing pre-clinical and clinical
research on immune tolerance in autoimmunity and the potential for collaborative
efforts is promising.
Current NIAID efforts to develop collaborations with companies for pilot
clinical trials will lay the groundwork for cooperative, multi-site Phase
II and III clinical trials using this infrastructure. In addition, the
participation of other NIH Institutes will be encouraged and pursued.
C. ASTHMA AND ALLERGIC DISEASES
Asthma and allergic diseases are attractive models for development of
new approaches to alter the human immune response. These diseases are
increasing in prevalence and account for high medical and social costs.
Despite the availability of proven therapies and many new agents in development,
even the most effective pharmacotherapies have serious limitations. Some
data suggest that either reduced allergen exposure, or conventional allergen
immunotherapy, can block the development of asthma and/or exacerbations
of asthma. However, there are obstacles to translating these findings
into clinical practice, perhaps because present approaches to environmental
control do not sufficiently reduce allergen levels, and because conventional
immunotherapy causes only weak modulation of the human immune response.
The most promising approach is to develop new methods of inhibiting allergic
immune responses and/or inducing tolerance to allergens.
The development of new approaches would be enhanced by the many widely
available, well standardized and clinically validated tests, including
blood studies, skin tests, and pulmonary function tests, that can be used
to characterize allergic responses from the immunological and physiological
perspectives. Moreover, it may soon be possible to enhance the identification
and stratification of at-risk individuals based on the discovery of genes
that predispose to asthma and atopy.
Allergen immunotherapy was developed empirically ~80 years ago and relatively
little effort has been made to develop more robust and long-lasting allergen
immunotherapies, based on fundamental principles of immunology. However,
concerns about the efficacy of conventional immunotherapy have stimulated
research into new approaches to tolerize to allergen. A variety of avenues
are being explored and build on the fact that many clinically important
allergens have been identified, purified, cloned, epitope-mapped, produced
as biologically active recombinant proteins, and administered safely by
mucosal and cutaneous routes. With these reagents, the timing, dose, route,
and molecular form for the allergen can be tightly controlled. Approaches
that combine non-antigen specific methods (e.g., second signal blockade
and cytokine modulation) and antigen-specific tolerance appear very promising
in animal models and are close to entering Phase I and/or Phase II clinical
studies in man. Among these are: 1) "DNA vaccines" comprised of plasmid
DNA encoding recombinant allergens, which induce long-lasting allergen-specific
tolerance in mice; 2) immunostimulatory oligonucleotides, small sequences
of bacterial DNA that drive the Th1 immune responses when co-administered
with protein allergens; 3) T cell co-stimulatory blockade in conjunction
with allergen challenge; 4) peptide vaccines representing T cell epitopes
of allergen; 5) immunization with Mycobacterium vaccae, which non-specifically
drives Th1 immune responses; 6) monoclonal antibodies to IgE, which deplete
plasma IgE and down-regulate mast cells and basophil receptors for IgE;
and 7) co-administration of allergen and cytokines.
Asthma and Allergic Diseases: Specific Initiatives
- NIAID Cooperative Clinical Trial in Allergen Immunotherapy
- Multidisciplinary Research Centers in Asthma and Allergic Diseases
Asthma and Allergic Diseases: Detailed Research Plan
NIAID Cooperative Clinical Trial in Allergen Immunotherapy
The establishment of a Cooperative Clinical Trial in Allergen Immunotherapy
will provide the infrastructure to capitalize on current opportunities
to evaluate tolerogenic approaches for the treatment of human allergic
diseases. With such a program, standardized clinical trials at all phases
would be carried out by clinical investigators in cooperation with basic
immunologists to assess safety, efficacy, mechanisms of action, and therapeutic
effect of multiple approaches, including second signal blockade, DNA,
oligonucleotide and microbial adjuvants, and co-administration of cytokines.
The Cooperative Clinical Trial in Allergen Immunotherapy would be linked
to the Human Immunology Cooperative Study Groups to support basic and
mechanistic studies of new allergen immunotherapies.
Multidisciplinary Research Centers in Asthma and Allergic Diseases
To facilitate future discovery, a network of Research Centers will be
important for the development and testing of new reagents and approaches
for tolerizing human allergic responses. The basic and translational research
conducted by these Centers would span many disciplines (e.g., T and B
cell immunology; antigen [allergen] processing and presentation; biology
and function of mast cells, eosinophils, and basophils; high-resolution
structural studies of allergens; and vaccinology) with the ultimate aim
of discovering new tolerizing approaches. Shared resource cores (e.g.,
for the purification of allergens or for production and modification of
recombinant allergens; for structural characterization of allergens; for
production of DNA vaccines and other DNA-based therapies; and for testing
experimental therapies in appropriate animal models) would serve all Research
Centers in the network.
D. CROSS-CUTTING RESEARCH
HUMAN IMMUNOLOGY COOPERATIVE STUDY GROUPS
The establishment of Human Immunology Cooperative Study Groups is a critical
component of this research plan and will provide the techniques and data
essential for the design of immune tolerance protocols, including standardized
assays and reliable markers of tolerance. The NIAID Cooperative Clinical
Trial in Adult Kidney Transplantation has identified sensitive predictors
of rejection and delineated some immunologic parameters involved in both
rejection and graft survival. However, these results are still preliminary
and additional resources will be required to: expand this line of investigation
in transplantation, autoimmunity and allergic diseases; focus additional
efforts directly on immune tolerance; and provide the cooperative infrastructure
necessary to conduct research using common approaches and standardized
techniques. This Group will serve as a central resource for studies conducted
by the NIAID Cooperative Clinical Trials in Kidney Transplantation, Islet
Transplantation, Autoimmune Diseases, and Asthma and Allergic Diseases,
as well as clinical and non-human primate studies conducted by other NIAID
grantees. Examples of research areas that might be supported include:
- The development of markers for the induction, maintenance and loss
of tolerance.
- Assessment of the mechanisms of action of tolerogenic reagents being
tested in pre-clinical and clinical studies.
- Studies to define the immunological mechanisms of immune-mediated
diseases and the acceptance, survival and rejection of transplanted
solid organs and cells.
- Further development of non-invasive alternatives to surveillance biopsies
to assess graft function and predict rejection (e.g., peripheral blood
and urine).
- Development and application of DNA/microarray chip technologies.
A joint Task Force on Transplantation Tolerance, convened by the American
Society of Transplant Physicians (ASTP) and the American Society of Transplant
Surgeons (ASTS), held its first meeting in October 1997. The goal of this
joint effort is to develop guidelines and projects to facilitate the application
of tolerogenic approaches in the transplant setting. The participants
agreed on the importance of establishing an NIH-supported cooperative
group to develop markers and assays for studies of human immune tolerance.
RESEARCH RESOURCES
Translation of the basic immunological principles of tolerance to clinical
applications will require greater coordination of research and resources
than is currently in place. This will entail development of the appropriate
infrastructure to facilitate investigator interactions and enable ready
access to research resources. Specific components of the research plan
include:
- Establishment of a Good Manufacturing Practice Facility to produce
and distribute promising tolerogenic molecules to NIAID-supported investigators
for basic, preclinical and clinical studies.
- Expansion of NIAID's program for the breeding and distribution of
transgenic and knock-out mice for studies of immune tolerance.
- Support for the breeding and maintenance of non-human primates through
the Regional Primate Centers of the National Center for Research Resources.
- Research Training Programs.
Good Manufacturing Practice Facility
A Good Manufacturing Practice (GMP) Facility will expand the availability
of promising tolerogenic molecules and, in doing so, accelerate their
evaluation in pre-clinical studies, clinical trials, and more fundamental
investigations of mechanisms of action. Such a facility will ensure the
timely availability of immunologically important materials for NIAID-supported
investigators and will be important in advancing research on immune tolerance
for several reasons. It will allow studies of mechanisms of action in
cases where industry is unable or unwilling to pursue this line of investigation.
In addition, it will permit the NIAID to sponsor further research in cases
where industry has abandoned product development. For small companies,
the costs of producing reagents is often prohibitive and, in other cases,
preliminary discussions with industry suggest that licensing research
materials to the NIAID may be contingent upon the Institute's capacity
for further production. Finally, in many instances, an individual investigator
lacks the resources to produce these materials in-house.
Mouse Breeding and Distribution
NIAID currently supports the importation, breeding and distribution of
immunologically relevant, unique gene-knockout and transgenic mouse strains
for the extramural research community. This program will be expanded to
provide early access to additional mouse strains already developed as
models for transplantation, autoimmune and allergic diseases, and to animals
that will be useful for new model development. These may include "humanized"
mice that express one or more human molecules, such as CD4, CD8, MHC I
or II, to increase the similarities of mouse models to human disease,
or mice that express genetically engineered co-stimulatory molecules or
signal transduction components thought to play a role in the induction
or maintenance of tolerance.
Breeding and Maintenance of Non-Human Primates
The breeding and maintenance of non-human primates can be supported efficiently
through the seven Regional Primate Centers funded in part by the National
Center for Research Resources (NCRR). In supporting these Centers, NCRR
provides funds for administrative costs, the building and maintenance
of facilities, and approximately 40 percent of staff salaries. Since a
substantial portion of the costs associated with these Centers is already
supported by NCRR, using these existing facilities would provide a more
cost-efficient method for breeding and maintaining non-human primates
for research on immune tolerance. Support can be provided from grant or
contract funds and direct NIAID financing will eliminate the indirect
costs associated with purchasing such services on the part of individual
academic institutions.
Research Training Programs
Ensuring an adequate supply of well trained and highly qualified basic
scientists and clinical researchers is an important aspect of the ability
to continue to accelerate research in this area. Training needs are particularly
critical for translational research, underlying mechanism studies, and
the design and conduct of clinical trials. New clinical training programs
recently established by the NIH Director will be used to provide career
development support in these areas. Additional opportunities will be pursued,
including the incorporation of career development support within some
of the research programs to be established.
EXPLORATORY/DEVELOPMENTAL RESEARCH PROJECTS
Establishment of an innovative research grant program will provide short-term
support for a variety of pilot projects to establish truly novel areas
of immune tolerance research. The objective of this program is to produce
preliminary data that validate innovative but, as yet, speculative tolerance
concepts or clinical feasibility in basic, pre-clinical or clinical areas
of tolerance research. Successful grants will provide the foundation for
future projects to be pursued using conventional funding mechanisms. It
is expected that this program will broaden the base of scientific discovery
by encouraging the rapid development of new ideas and by attracting investigators
previously outside the tolerance field.
Examples of specific areas of research to be supported by this program
include:
- Novel targets to divert signal transduction pathways.
- Cell or tissue engineering to induce tolerance versus immunity.
- Innovative technical approaches to monitor tolerance induction and
maintenance in vivo.
- Novel diagnostic techniques for more rigorous classification of immune-mediated
diseases.
- New animal models of immune-mediated human disease.
BASIC STUDIES FOR FUTURE DISCOVERY
Support for multidisciplinary projects will expand knowledge of the molecular
basis for tolerance induction and maintenance in animal and human systems.
Examples of the types of research to be supported include:
- Definitive studies on the mechanisms by which currently effective
or promising biological and pharmaceutical agents produce tolerance
in vitro or in vivo and factors that might limit their usefulness in
clinical applications.
- The identification and characterization of promising new targets of
tolerance induction.
- The basis for differences in tolerance induced by mucosal versus systemic
routes.
- The molecular mechanisms responsible for the loss of tolerance to
specific antigens.
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