4. Report of Division of Allergy, Immunology, and Transplantation Council Subcommittee

Daniel Rotrosen, M.D., Director, DAIT

Dr. Rotrosen announced the following new staff members and scientific activities:
Nasrin Nabavi, Ph.D. Dr. Nabavi joined the Division in June as a Program Officer in the Basic Immunology Branch after serving 3 years as a Scientific Review Administrator in the NIAID, Division of Extramural Activities. Prior to NIH, Dr. Nabavi was an Associate Professor at the Medical University of South Carolina and a Senior Scientist at Roche Research Center in New Jersey.

Faraz Nasseri, Ph.D. Dr. Nasseri joined the Division in July as a Program Officer in the Basic Immunology Branch. Dr. Nasseri received his Ph.D. from UCLA, studying the oncogenesis and pathogenesis of papillomaviruses using animal models and cell cultures, and completed a post-doctoral fellowship at the University of Rochester and at Stanford University.

Lara R. Miller, B.A. Ms. Miller joined the Basic Immunology Branch in June as a Health Specialist. Her previous experience includes data coordination for an NIAID-supported tuberculosis screening program and, more recently, as a Quality Control Biologist for the Frederick Brewing Company. She received her Bachelor's degree in biology from Hood College and is pursuing her Master's degree in environmental biology, also at Hood College.

Beverly Welch, RN. Ms. Welch joined the Clinical Immunology Branch in June, as a nurse consultant for the autoimmune stem cell and ACE clinical trials. Prior to coming to NIAID, Ms. Welch served as a staff nurse and study coordinator overseeing clinical trials in the areas of rheumatology and transplantation (solid organ and bone marrow) from 1987 through 1999, at the Georgetown University Medical Center and Arlington Hospital. She received her BS degree in nursing from the University of Delaware in 1987, and received her Master's degree in nursing administration from Georgetown University in 1991.

John Guzman, B.S. Mr. Guzman joined the Office of Clinical Applications as a Regulatory Specialist in July. Previously, Mr. Guzman worked for Nabi Biopharmaceuticals in Rockville, MD, as a Regulatory Specialist on Nabi's NicVAX (nicotine vaccine) project. Prior to Nabi, he worked for the Food and Drug Administration in the Center for Drug Evaluation and Research as a Regulatory Health Project Manager in the Division of Cardio-Renal Drug Products. He received his degree in biochemistry from the University of Maryland, College Park, and his MS in Biotechnology from the Johns Hopkins University.

V. K. Skaare, MSN, RN, CCTC. Ms. Skaare joined the Office of Clinical Applications in July as Nurse Consultant/Project Manager. Prior to joining the Division, Ms. Skaare's nursing career included patient care, liver and kidney transplantation coordination, and managing clinical trials protocols. She is a graduate of George Mason University with a MS in Nursing and a graduate teaching certificate.

Elizabeth Schneider, B.S. Ms. Schneider joined the Office of Clinical Applications in May as a Health Specialist for clinical trials conducted by the Immune Tolerance Network (ITN). Her responsibilities include protocol development and implementation of ITN transplant and autoimmunity trials.
Mrs. Schneider has prior research experience as a monitor and a project manager in the following areas: Vaccine Development, Cardiovascular Studies, and Arthritis. She received her BS degree in physical therapy from the University of Connecticut.

David R. Johnson, Ph.D. Dr. Johnson joined the Clinical Immunology Branch in August as a Program Officer in the Autoimmunity Section. Dr. Johnson earned his Ph.D. in immunology from Columbia University and held research fellowships at Harvard University and the Brigham and Women's Hospital. Prior to his appointment, he served on the faculty at Yale University, where he studied cytokine regulation of the HLA class I loci and antigen presentation by endothelial cells.

Helena Chepkwurui, B.S. Ms. Chepkwurui joined the Office of Clinical Applications, in May, as Project Manager. Prior to coming to NIAID, Ms. Chepkwurui worked as a Regulatory Affairs Coordinator for the HIV Clinical Interventions Program at Walter Reed Army Medical Center. She has also worked with HIV projects/programs in Uganda. She received her BS degree in biology from the University of Maryland, Eastern Shore, and is currently pursuing a MS degree in public health/international health.

Joy Laurienzo, R.N., CCRC. Ms. Laurienzo joined the Asthma, Allergy and Inflammation Branch (AAIB) in August as a Nurse Consultant and will be responsible for managing clinical trials conducted by the ITN and AAIB. She received her BS in Nursing from the University of Maryland and recently worked as a Clinical Research Coordinator at the Washington Hospital Center, managing large multi-center clinical trials. She has also worked at the NIH Clinical Center in the Echocardiography Laboratory of the National Heart, Lung, and Blood Institute, supervising laboratory operations and coordinating intramural research protocols, as well as multi-center clinical trials.

Scientific Initiatives

Expansion of NIAID Biodefense Research Program
The NIAID recently published several initiatives in the NIH Guide to Grants and Contracts to encourage submission of grant applications on biodefense research, including projects focused on innate and adaptive immunology in the context of CDC category A-C agents of bioterrorism. Detailed information is available at http://www.niaid.nih.gov/publications/bioterrorism.htm.

Hyperaccelerated Award/Mechanisms in Immunomodulation Trials: Expansion of RFA:AI-02-003 to Include Biodefense Research. The NIAID issued a Notice in the Guide to expand support for investigator-initiated mechanistic studies in clinical trials of vaccines focused on Category A-C agents of bioterrorism and emerging/re-emerging infectious diseases.

Autoimmunity Centers of Excellence: The NIAID, National Institute of Diabetes and Digestive and Kidney Diseases and the Office of Research on Women's Health invite applications for Autoimmunity Centers of Excellence (ACEs). The purpose of this cooperative research program is to support integrated basic, pre-clinical and clinical research centers to: conduct single site and multi-site cooperative clinical trials and studies of mechanisms of action of tolerance induction and new immune modulation interventions in multiple autoimmune diseases; accelerate early translation of basic findings into clinical application; facilitate the utilization of clinical materials for basic research studies; enhance the exchange of information between basic scientists and clinicians and among various specialists involved in treating autoimmune diseases; and establish a collaborative approach to clinical and basic research among multiple institutions in various geographic areas.

Innovative Partnerships in Type 1 Diabetes Research: The NIAID expects to fund several R21 grant applications received in response to this Request for Applications (RFA), which was issued in collaboration with the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Eye Institute (NEI), National Institute of Nursing Research (NINR), and National Heart, Lung, and Blood Institute (NHLBI). The applications addressed many topics ranging from fundamental research on etiology and pathogenesis of type 1 diabetes to applied research focused on the development of methods for the prevention, detection, diagnosis, improved treatment, and cure. These grants will support collaborations between investigators experienced in type 1 diabetes research and its complications and investigators from other areas with relevant expertise. These interdisciplinary partnerships have attracted new investigators to research on type 1 diabetes and will strengthen the ongoing efforts of established type 1 diabetes researchers. This initiative is supported by type 1 diabetes research special appropriation.

Bench to Bedside Research on Type 1 Diabetes and its Complications: The NIAID expects to fund several R21 grant applications received in response to this Request for Applications (RFA), which was issued in collaboration with the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Eye Institute (NEI), and National Heart, Lung, and Blood Institute (NHLBI). These grants will support partnerships between clinical and basic biomedical researchers with the goal of more quickly translating advances in understanding of the molecular basis of type 1 diabetes and its complications into new therapies for the prevention, treatment and cure of this disease. Successful "bench to bedside" research partnerships, will bring basic research advances from the laboratory to a point where promising new therapies can be tested in clinical trials with patients or in preclinical studies in animal models. This initiative is supported by type 1 diabetes research special appropriation.

Division Activities

Probiotics and Asthma/Allergy Prevention: NIAID and the NIH Office of Dietary Supplements are sponsoring a workshop, "Prevention of Asthma and Allergy with Probiotics," on September 26. This workshop will review the effects of probiotics on the immune systems, including their potential for modulation of systemic and gastrointestinal immunity and their capacity to prevent atopic dermatitis, asthma, and allergies. The most promising direction for future research will be identified.

Atopic Dermatitis and Vaccinia Immunization Expert Panel: On June 18, the NIAID convened an Expert Panel on "Atopic Dermatitis and Vaccinia Immunization." The charge to the panel was to develop a research plan to reduce the risk of eczema vaccinatum (EV) associated with cutaneous dissemination of the vaccinia virus. EV is a major complication of vaccinia immunization and occurs almost exclusively in patients with atopic dermatitis (AD).

Expert Panel on Immunity and Biodefense: An Expert Panel was convened by NIAID on June 17, to address the immunological aspects of biodefense preparedness research. Approximately 25 internationally renowned scientists from academia and industry discussed high priority research areas in immunology that would lead to improved biodefense strategies, and recommended methods by which these research goals might be achieved. A summary of this meeting will be published on the NIAID web site.

Workshop on Class II MHC/Peptide Multimers: DAIT and the Division of AIDS sponsored a workshop, on June 18-19, to bring together leaders in the field to address major technical hurdles to the widespread use of class II MHC multimer reagents for T cell detection. The panel concluded that continued improvements in reagent design and specially tailored strategies for their application will emerge from basic studies of TCR-MHC interactions.

Vaccine Immunology Basic Research Centers Meeting: The NIAID convened a meeting, on September 12-13, focused on progress in vaccine immunology. The participants included investigators from Stanford University, Mount Sinai School of Medicine, Johns Hopkins University, and the University of Rochester who are currently funded by NIAID program projects in response to RFA AI-99-008 on the immunological basis of vaccines. Discussions included viral evasion of innate immunity, antigen processing and presentation in young children, and characterization of protective immune responses. The meeting highlighted the interactions of innate and adaptive immune mechanisms in vaccine immune responses.

American Transplant Congress: NIAID co-sponsored a symposium at the 2002 American Transplant Congress in Washington, D.C. This symposium, "Dendritic Cells/Cross Presentation," focused on mechanisms of antigen presentation that are involved in T-cell antigen recognition and allograft rejection.

Polyomavirus Allograft Nephropathy Workshop: On August 13-14, NIAID and the Office of Rare Diseases co-sponsored a workshop entitled "Polyomavirus Nephropathy in Immunosuppressed Kidney and Other Solid Organ Transplant Recipients." Investigators discussed the basic biology of polyomaviruses, the immune responses to polyomavirus infection, and the prevalence of polyomavirus allograft nephropathy (PVAN) in transplant recipients. The exchange of data, techniques, and ideas facilitated collaborations to address outstanding needs, including: (1) identifying markers of PVAN and developing new, noninvasive methods of polyomavirus detection; (2) determining the role of intensive immunosuppression as a causative agent in PVAN; and (3) analyzing therapeutic regimens for the treatment of PVAN.

Workshop on Autoantibodies as Predictors of Autoimmune Diseases: NIAID, with the Office of Rare Diseases, the Office of Women's Health, and the American Autoimmune Related Diseases Association, sponsored a workshop on September 12-13, to discuss the potential value of autoantibodies as predictive markers for development of autoimmune diseases. While the value of autoantibodies in determination of risk for development of type 1 diabetes has been shown, their value as predictors for development of other autoimmune diseases is unclear. The participants addressed current data on autoantibodies in development of a number of diseases, including celiac disease, Addison's disease, autoimmune hepatitis, Sjogren's syndrome, SLE, and pemphigus. The standardization and validation of assays, including the development of high throughput methodologies and novel strategies for assaying autoantibodies was discussed. Participants highlighted further data needed to determine risk and the most promising approaches for using autoantibodies in risk assessment.

Concept Review

All concepts were presented and approved.

Biodefense

Cooperative Centers for Translational Research on Human Immunology and Biodefense: This program will support an expanded centralized research infrastructure to develop, standardize, and apply appropriate reagents, assays, and technologies to the study of human immunity. The Centers will facilitate translation from animal studies to human studies, and translation from basic research to clinical applications. In addition, novel research projects will be supported to investigate the molecular control of immunoregulation in the human, and to identify immunotherapeutic targets relevant to the prevention of disease caused by, or control of, CDC Category A-C pathogens and their toxins. A training program for clinical fellows and visiting scientists is also included. Each Center will focus on a particular area of human immunity, such as innate immune mechanisms of protection or long-term immune memory, and will provide specialized expertise in the area and develop new methods for use by the Centers network and the scientific research community.

Innate Immune Receptors and Adjuvant Discovery: This program will support three major areas of investigation that focus on the innate immune system and adjuvant discovery: 1) discovery of novel innate immune receptors and/or mediators; 2) high-throughput analysis of cellular responses to adjuvants and innate receptors; and 3) preclinical analysis and first-in-human testing of promising new innate immune adjuvant candidates.

Population Genetic Analysis Program: Immunity to Vaccines/Infections: This program will support studies on human genetic polymorphisms, that is, alternate forms of genes, associated with host immune responsiveness to infections and vaccination. The focus will be on CDC Category A-C pathogens. Materials for such studies will be obtained from patients with a history of natural infections; individuals currently enrolled in vaccine trials; and/or previously vaccinated high-risk groups, such as military, laboratory, and health care personnel. In addition, efforts will be made to include at-risk groups such as the very young, the elderly, and individuals with immunodeficiencies. Genomic information from mouse model systems can be used to facilitate identification of relevant human immune response genes. Particular emphasis is placed on studies identifying host immune factors that play a role in controlling, protecting, or predisposing to an infection; exacerbating disease; determining resistance to treatments; or that might serve as targets for passive immunotherapy. Interdisciplinary teams that combine diverse scientific expertise (e.g., microbiology, immunology, genetics, mathematics, computer science) will be encouraged.

Large Scale Antibody and T Cell Epitope Discovery Program: This program will consist of: 1) identification of linear and conformational antibody epitopes; 2) identification of T cell epitopes that bind class I, class II, and non-classical MHC molecules; 3) definition of peptide binding motifs on a sufficient number of HLA alleles to cover the human population worldwide; and 4) design and development of novel or improved high throughput screening assays for antibody and/or T cell epitope discovery that are easily transferable to the broader scientific community, thus providing standardized methods to facilitate more rapid discovery.

Reagent Development for Monitoring Immunity in Non-Human Primates: This initiative will support the development of reagents for analyzing the immune response, develop technologies for immune monitoring, and develop high-throughput techniques for MHC typing in non-human primates. Immune monitoring reagents will be developed for candidate proteins to which monoclonal antibodies or soluble, recombinant, or multimeric molecules are desired, utilizing currently available genetic constructs or de novo recombinant DNA strategies. MHC typing will involve strategies to characterize the MHC loci of several NHP species, design and test DNA primers and probes that distinguish these MHC alleles, and develop technologies for rapid, high-throughput MHC typing.

Hyperaccelerated Award/Mechanisms in Immunomodulation Trials: The renewal of this program will incorporate the same elements pioneered by NIAID in FY 1999 to facilitate submission, peer review, and award of successful applications as early as 13 weeks of receipt, including: 1) monthly receipt of applications; 2) monthly internet- and teleconference-based peer review; 3) negotiated assignments among participating ICs; and 4) expedited council approval.

This renewal will also incorporate all aspects of RFA AI-02-003, released March 2002, in addition to NOT-AI-02-034, released July 2002, to expand funds available to mechanistic immunological studies in clinical trials of vaccine candidates for CDC Category A-C pathogens.

Immunological studies focus on the inclusion of samples and data from clinical trial patients for: the evaluation of immunologic and other relevant parameters to facilitate the study and definition of immunological mechanisms underlying the intervention: the evaluation of the underlying immune mechanisms of effective responses to candidate vaccines; definition and characterization of the mechanisms of disease pathogenesis; and definition of surrogate/biomarkers of disease stage, activity and therapeutic effect.

Proposed mechanistic studies associated with clinical trials supported by industry are particularly encouraged; however, clinical trials supported by any source, public or private, are eligible.

Bioinformatics Integration Support Contract, (BISC): BISC supports the bioinformatics needs of several established and new programs of DAIT. Services are performed by a competitively selected contractor, including: (a) conducting a requirements assessment of bioinformatics needs in the targeted programs; (b) designing, implementing, and maintaining a data warehouse of genomic and other related data relevant to the research of these programs; (c) providing technical assistance to participating centers in the selection of technologies for the capture, storage, query, and analysis of these data; and (d) measuring performance and benefits resulting from these technical support activities and planning for their appropriate use in the future. Once established, this platform may be extended to include additional types of data and analyses.

Non-Biodefense

Clinical Trials in Organ Transplantation: This new initiative will complement NIAID's multi-center cooperative clinical trials program to evaluate novel and innovative therapeutic approaches for enhancing solid organ or tissue transplantation in patients with end-stage organ disease. For each organ or tissue, the cooperative clinical centers will select, by consensus: 1) common therapeutic protocols for immunosuppression; 2) standards for immune monitoring of transplant recipients; and 3) candidate surrogate markers to predict graft rejection. Participating centers will enroll and monitor eligible patients in these studies. A data and safety monitoring board will review the clinical protocols and adjunct studies. Because of the importance of the immune system in graft acceptance and rejection, this initiative also seeks to increase basic knowledge of organ-specific immunity and promote the application of such knowledge in the clinical setting.

Immune System Development and the Genesis of Asthma: This initiative focusing on stimulating research on the immune system in early life to define the cellular and molecular mechanisms underlying the development of asthma and to devise strategies for the effective prevention or reversal of disease without compromising the integrity of the immune system. Investigations will focus on: 1) early cellular and molecular markers of asthma onset and progression; 2) factors that regulate the processing and presentation of aeroallergens in the fetal or infant lung; 3) mechanisms involved in the initiation and amplification of aeroallergen-specific IgE synthesis; 4) time course and regulation of primary B and T cell (Th1/Th2, regulatory and cytotoxic) responses; 5) the role of the innate immune system in determining susceptibility to asthma; and 6) the effects of maternal and environmental asthma-related risk factors (e.g., maternal atopy, environmental tobacco smoke, diesel exhaust particles) on immune function in early life.

Innovative Grants on Immune Tolerance: This initiative is to support innovative exploratory/developmental research project grants on novel studies of the molecular mechanisms and applications of immune tolerance. The focus is on the antigen-selective and long-term inactivation of immune responses. Projects funded under this program will have a high degree of innovation and have a clearly articulated potential to improve understanding of the mechanisms of immune tolerance. Investigators new to immune tolerance research are especially encouraged to develop projects in this area. Research projects will be supported by the exploratory/developmental research grant mechanism, which provides the resources to carry out preliminary tests of feasibility for new research hypotheses.

Genomics of Transplantation: This initiative will support a cooperative network of investigators from diverse backgrounds, including: molecular biologists; population geneticists; immunologists; transplant clinicians and researchers; statisticians; and informatics specialists to conduct research directed at: 1) pharmacogenetic analysis of microsatellite and single nucleotide polymorphisms (SNPs), as well as SNP haplotypes, in candidate genes of both transplant donors and recipients, and correlation of these genetic variations with responses to immunosuppression protocols; 2) delineation of microsatellite polymorphisms, SNPs, and SNP haplotypes in candidate genes and unique gene expression patterns in minority populations who are at risk of lower graft survival; 3) analysis of gene polymorphisms, including cDNA microarrays, to identify and characterize immune response genes expressed during acute and chronic graft rejection that relate to onset and severity of graft rejection; and 4) statistical and bioinformatics approaches to analyze multiple gene interactions. These studies will utilize recipient and donor blood and tissue samples, as well as clinical information, from both retrospective and concurrent clinical trials in transplantation.

Diagnosis and Treatment of Polyomavirus Allograft Nephropathy, (PVAN): This program will support pre-clinical and clinical research on PVAN in renal and other solid organ transplantation. Projects will address outstanding issues including: 1) identification of PVAN biomarkers; 2) determination of PVAN prevalence in renal or other solid organ transplant recipients; 3) development of new diagnostic assays for PVAN; 4) elucidation of the host immune response to polyomavirus; 5) development of PVAN animal models for evaluation of therapeutic strategies; and 6) initial and long-term follow-up of the viral and immune response status of transplant recipients undergoing treatment for polyomavirus infection or nephropathy. Overall, this initiative will enable the design of clinical protocols directed at the prevention and treatment of PVAN.

Multiple Autoimmune Diseases Genetics Consortium: The purpose of this solicitation is to continue the Multiple Autoimmune Diseases Genetics Consortium (MADGC), a core facility dedicated to the collection and characterization of families in which two or more affected individuals are affected by two or more autoimmune diseases. The facility operates two simultaneous activities: a registry for families that collects, validates, and updates clinical, demographic, and laboratory data; and a repository of immortalized cells and DNA samples from the enrolled family members. The contents of the database, cells, and DNA samples are available to basic and clinical researchers. The facility also maintains a database of published genotypic data on these families. The renewal would include genotyping of all samples, continued follow-up of unaffected individuals to identify those that later develop autoimmune disease, collection of additional families, and funding for pilot projects to use the resource.

Autoimmunity Centers of Excellence: This initiative will renew NIAID's highly successful Autoimmunity Centers of Excellence (ACEs), a cooperative network of integrated basic, pre-clinical, and clinical research centers that: conduct single site and multi-site cooperative clinical trials and studies of mechanisms of action of tolerance induction and new immune modulation interventions in multiple autoimmune diseases; accelerate early translation of basic findings into clinical application, facilitate the utilization of clinical materials for basic research studies; enhance the exchange of information between basic scientists and clinicians and among various specialists involved in treating autoimmune diseases; and promote a collaborative approach to clinical and basic research among multiple institutions in various geographic areas.