Scripps Research Logo

Research

The focus of our laboratory is the genetic basis of systemic autoimmunity, and the diversity of T-cell repertoires in disease states.

Transgenic and Gene Knockout Lupus Strains

To address the role of specific immune-related genes in the pathogenesis of lupus, we are generating lupus background transgenic and gene knockout congenic lines. Studies in such mice have demonstrated that: a) TCR BV allelic exclusion is not complete, dual BV expressing cells are present in older mice, and the frequency in such cells is expedited in lupus mice; b) the double negative cells of lpr mice are highly functional and the p59fyn kinase is required for their activation; and c) IFN-g is an important cytokine for the development of lupus.

Apoptosis and Cell-Cycle Genes in Lupus

A major focus of our laboratory is to define the roles of apoptosis and cell-cycle genes in autoimmune states. We have shown that the activation/memory phenotype T cells, which accumulate in lupus, are refractory to TCR-induced proliferation, resistant to activation-induced cell death and the majority are arrested at the G1 phase. These characteristics were associated with enhanced expression of cyclin kinase inhibitors and Bcl-XL. A combination of high expression of cell cycle and apoptosis inhibitors appears to lead to the survival of memory phenotype T cells that are in a state similar to replicative senescence. These cells may contribute to disease by secretion of disease-promoting cytokines.

Autoimmune Susceptibility Genes

Our laboratory is currently defining the genetics for the major lupus strains of mice that include the NZB, NZW, MRL-lpr, C57BL/6-lpr, and BXSB. Studies have generated comprehensive locus maps, demonstrated a multiplicative mode of inheritance and shown that loci contribute to different stages or checkpoints of lupus pathogenesis. Current studies are extending this work to identify the genes themselves, to dissect genetic heterogeneity and to define the mechanisms important for autoimmune susceptibility.

T Cell Repertoires in Lung Transplantation and Cancer

We have identified clonal or oligoclonal population expansions of T cells in lymphocytes of peripheral blood and bronchoalveolar lavage from lung transplant recipients. The prominence of finite, distinct TCR phenotypes raises possibilities for development of novel diagnostic modalities and targeted immunotherapies for obliterative bronchiolitis and other manifestations of chronic allograft rejection.

We have also shown that the T cell repertoires of lung cancer patients have marked abnormalities and frequent clonal expansions, most likely representing responses to unique tumor-associated antigens (TAA). We are currently attempting to clone lung cancer-specific genes encoding such TAA.

___________

Home
___________

Research
___________

Personnel
___________

Publications
___________