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NIAID and NIH Office of Rare Diseases Workshop on Systemic Vasculitis: Future Research Directions

Summary and Recommendations

Contents

Workshop Summary

On September 15, 1997, the National Institute of Allergy and Infectious Diseases and the National Institutes of Health Office of Rare Diseases convened a workshop on Systemic Vasculitis at the National Institutes of Health. The primary vasculitis syndromes are a group of rare diseases thought to be caused by immune system mediated inflammation and necrosis of blood vessels leading to vessel occlusion and ischemia of tissues supplied by affected vessels. Examples include polyarteritis nodosa, Wegener’s granulomatosis, microscopic polyangiitis, giant cell arteritis, and Takayasu’s arteritis. The workshop brought together a group of distinguished scientists (Appendix) to consider the currently available information and to make recommendations as to the most exciting and fruitful research opportunities and approaches for determining the pathogenic mechanisms underlying this group of rare diseases.

The currently available information was reviewed in a series of presentations by the participating scientists. Following an overview of the unresolved issues in the diagnosis and treatment of systemic vasculitis (Dr. Hoffman), the first group of presentations focused on pathogenic mechanisms and molecules in various forms of systemic vasculitis including: integrins and leukocyte adherence (Dr. Arnaout), anti-neutrophil cytoplasmic antibodies (Dr. Falk), Fc receptor polymorphisms (Dr. Kimberly), superantigen vs. conventional antigen in Kawasaki Disease (Dr. Hirsch), and T lymphocytes, cytokines, and mediators (Dr. Weyand). The second group of presentations focused on mechanisms and molecules of inflammation including: vascular endothelial cells as stimulators and targets of immune responses (Dr. Bender), adhesion molecules evaluated using deficient mice (Dr. Bullard), leukocyte stiffening in sequestration and emigration (Dr. Doerschuk), reactive nitrogen intermediates and genes which confer protection to them (Dr. Nathan), the anti-inflammatory phospholipase called plasma platelet activating factor acetylhydrolase (Dr. Prescott), and phagocyte produced molecules which cause tissue destruction (Dr. Weiss).

While it was evident that progress in the understanding of the systemic vasculitis syndromes had been made, the participants concluded that considerable information is lacking including identification of etiologic agents, characterization of pathogenic pathways, and development of effective new interventions. Moreover, research in this area is difficult because of the rarity of the diseases and the relative paucity of animal models. However, the participants agreed that advances in immunology, molecular biology, and biotechnology offered excellent new research opportunities and approaches. They recommended the following areas:

Research Recommendations

Assessment for Infectious Etiologic Agents

Based on success in other diseases (e.g., H. pylori in gastric ulcers and Whipple Disease) and the availability of modern microbiologic approaches such as organism-specific or "kingdom"-specific PCR, the participants felt there was a real opportunity to identify an agent in at least some of the vasculitis syndromes. Other approaches that were suggested were epidemiological studies and the cloning of antigen-specific T lymphocytes from vasculitis lesions.

Identification of Genetic Polymorphisms Which Confer Resistance or Susceptibility

Inflammatory responses involve a large number of molecules including cytokines and cytokine receptors, adhesion molecules, costimulatory molecules, and signaling molecules. This offers the opportunity to identify and evaluate polymorphisms and analyze them for genetic linkage to disease.

Characterization of Activated Genes in Vasculitis Lesions

Use of high throughput technologies (e.g., chip technology using expressed sequence tags) and other modern in situ techniques to identify and evaluate genes activated in disease sites represents an opportunity to identify new important molecules and to evaluate which inflammation pathways are most relevant for the disease process.

Exploration of the Role of Lymphocytes and Phagocytes in the Development of Vasculitis

Isolation of cells from lesions and an assessment of gene expression by PCR and/or of cell surface markers by FACS will allow a more precise understanding of their function, targeting and regulation in the vasculitis disease process.

Identification of Injury Resistance Genes

Identification of antagonists to reactive oxygen intermediates suggests an opportunity to discover resistance mechanisms and injury resistance genes for other tissue destructive molecules that are important in vasculitis.

New Therapeutic Agents

The need for less toxic, remission-inducing agents was stressed. Empiric pilot trials of such agents as NFk B inhibitors and TNFa binding molecules were encouraged. It was emphasized that such trials would offer the opportunity to conduct informative mechanistic studies. The value of a network for such trials and for the acquisition of samples was strongly underscored. In addition, the suggestion was made that a tissue bank for such samples be considered.

NAIDI and ORD Workshop on Systemic Vasculitis: Future Directions

Appendix

Chairs

Howard B. Dickler, M. D.
Chief, Clinical Immunology Branch
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4A-19
National Institutes of Health
Bethesda, MD 20892-7640
Tel: 301-496-7104, Fax: 301-402-2571, Email: hd7e@nih.gov

Robert P. Kimberly, M.D.
Professor, Department of Medicine
University of Alabama at Birmingham
1900 University Ave., 429THT
Birmingham, AL 35294-0006
Tel: 205-934-5306, Fax: 205-934-1564, EMail: robert.kimberly@ccc.uab.edu

Speakers

M. Amin Arnaout, M.D.
Professor and Director, Leukocyte Biology and Inflammation Programs
Renal Unit, Department of Medicine
Massachusetts General Hospital and Harvard Medical School
149 13th Street
Charlestown, MA 02129-2000
Tel: 617-726-5666, Fax: 617-726-5669, Email: arnaout@motif.mgh.harvard.edu

R. Jeffrey Bender, M.D.
Associate Professor and Associate Chief, Cardiovascular Medicine
Boyer Center of Molecular Medicine
Yale University School of Medicine
295 Congress Ave., P.O. Box 9812
New Haven, Connecticut 06536-0812
Tel: 203-737-2223, Fax: 203-937-2293, Email: jeffrey_bender@quickmail.yale.edu

Daniel C. Bullard, Ph.D.
Associate Professor, Department of Comparative Medicine
University of Alabama at Birmingham
413 Volker Hall
1670 University Boulevard
Birmingham AL 35294-0019
Tel: 205-934-7768, Fax: 205-975-4419, Email: pike@uab.edu

Claire M. Doerschuk, M.D.
Associate Professor, Department Environment Health
Harvard School of Public Health
665 Huntington Ave.
Boston, MA 02115
Tel: 617-432-1706, Fax: 617-432-3468, Email: cdoersch@hsph.harvard.edu

Ronald J. Falk, M.D.
Associate Professor, Division of Nephrology
J. Thurston Professor of Medicine
Chief, Division of Nephrology
CB #7155, 3034 Old Clinical Building
Chapel Hill, NC 27599
Tel: 919-966-2561, Fax: 919-966-4251, Email: falkrj@med.unc.edu

Raphael Hirsch, M.D.
Associate Professor, Department of Rheumatology
PAV 2-129, Children's Hospital Medical Center
3333 Burnett Ave.
Cincinnati, OH 45229-3039
Tel: 513-559-4676, Fax: 513-636-4116, Email: hirschr@chmcc.org

Gary S. Hoffman, M.D.
Chairman, Department of Rheumatic and Immunologic Diseases
Cleveland Clinic, A-50
9500 Euclid Ave.
Cleveland, OH 44195
Tel: 216-445-6996, Fax: 216-445-7569, Email: hoffmag@cesmtp.ccf.org

Robert P. Kimberly, M.D.
Professor, Department of Medicine
University of Alabama at Birmingham
1900 University Ave., 429THT
Birmingham, AL 35294-0006
Tel: 205-934-5306, Fax: 205-934-1564, Email: robert.kimberly@ccc.uab.edu

Carl F. Nathan, M.D.
Stanton Griffis Professor of Medicine
Cornell University Medical College
1300 York Avenue, Box 57
New York, NY 10021-4896
Tel: 212-746-2985, Fax: 212-746-8536, Email: cnathan@med.cornell.edu

Stephen M. Prescott, M.D.
Professor, Eccles Institute for Human Genetics
University of Utah
Building 533, Room 4220
Salt Lake City, UT 84112
Tel: 801-585-3401, Fax: 801-585-6345, Email: steve.prescott@genetics.utah.edu

Stephen J. Weiss, M.D.
Upjohn Professor
Department of Medicine/MSRB III 5220D
University of Michigan Medical Center
1150 W Medical Center, Box 0640
Ann Arbor, MI 48109-0640
Tel: 313-764-0030, Fax: 313-764-0101, Email: SJWEISS@umich.edu

Cornelia M. Weyand, M.D., Ph.D.
Associate Professor of Medical Immunology
Mayo Clinic and Foundation
401 Guggenheim Building, Rheumatology
Rochester, MN 55905
Tel: 507-284-1650, Fax: 507-284-1086, Email: weyand.cornelia@mayo.edu

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Last Updated August 16, 2005