Chella S. David, D.Phil., Ph.D.

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SUMMARY

My research centers on immunogenetic aspects of immune response with emphasis on the major histocompatibility complex (MHC) HLA class I and II genes.

Transgenic mice expressing human MHC genes are used in structure/function analysis, disease correlation, and thymic regulation of T-cell development.

Major ongoing studies on HLA linked disease models are:

• Collagen-induced arthritis
• HLA-B27 linked spondyloarthropathies
• Experimental autoimmune encephalomyelitis
• Allergen-induced asthma
• Diabetes
• Lupus
• Celiac disease

Specific Research Topics

Expression and function of major histocompatibility genes. The broad interests of my lab are the studies on the regulation, expression, structure, and function of human major histocompatibility complex (HLA) class I and class II genes. During the past two years, we have focused on the following studies:

1. Role of human class II molecules in shaping the T cell repertoire.
2. The structure of class II molecules and their role in in vitro and in vivo immune responses.
3. Role of HLA class II genes and type II collagen epitopes in susceptibility to collagen induced arthritis - a model for human rheumatoid arthritis.
4. Role of human class I HLA-B27 transgenic mice in spondyloarthropathies.
5. Collaborative studies on the role of MHC class I and class II genes, and T cell receptor genes in the following humanized mouse models of disease:
   • Theiler's virus induced demyelination (with Dr. Moses Rodriguez)
   • Experimental autoimmune thyroiditis (with Dr. Yi-chi Kong)
   • Experimental autoimmune myasthenia gravis (with Dr. P. Christadoss)
   • New disease models for diabetes, lupus, allergy, multiple sclerosis, etc.

   The following studies are currently ongoing:

   • Mouse Model for Asthma. An induced asthma model using human allergens such as ragweed, house dust mite, and cockroach will be studied in the HLA class II transgenic mice. Role of CD4 and Th1 and Th2 cells in the pathology will be addressed.
   • Role of Natural Killer Cells in Spontaneous Arthritis in HLA-B27 Transgenic Mice: A Model for Human Spondyloarthropathy. In this model, transgenic mice expressing HLA-B27 and B27 specific KIRs (killer inhibitor receptors) will be studied where the disease is induced by MOG.
6. Experimental Autoimmune Encephalomyelitis. A Model for Human Multiple Sclerosis. The role of HLA class II genes in this model will be studied where the disease is induced by MOG.
7. A Mouse Model for Coeliac Disease. At this time, no mouse model exists for coeliac disease. Using HLA-DQ8 transgenic mice, we are trying to generate a mouse model for coeliac disease by orally feeding mice with gluten, a known human food allergen in the disease process.
8. HLA Transgenic Mouse Model for Type 1 Diabetes. We are developing two mouse models to study type 1 diabetes?an HLA class II restricted model in the context of rat insulin promoter/B7 costimulator, and a class I restricted model in the context of a rat insulin promoter/TNF.
9. Role of HLA Class II Molecules in Immune Response to Bacterial Superantigens. Humans are much more sensitive to bacterial toxins than mouse and is mediated by class II molecules.

   7. Collagen-induced Arthritis: A Model for Human Rheumatoid Arthritis. HLA transgenic mice in the CIA model.

10. Studies on Role of HLA Class II Genes in Human Lupus. The role of HLA-DR and -DQ genes in lupus will be studied by autoimmunity to nuclear antigens Ro60 in terms of T cell and B cell epitopes and antinuclear antibodies.
11. HLA Class II Restricted Mouse Model for Lupus. We have introduced HLA-DR2 and HLA-DR3 genes into NZB/W background to generate a human MHC linked spontaneous model for lupus.