Immunology Graduate Program | University of California, San Francisco

The research in my laboratory concerns the fundamental events that regulate T-cell activation and development during immune responses to autoantigens and transplantation antigens. Our efforts have focused on understanding the basic processes that control T cell activation and tolerance. We hope that the insights gained from these studies will help in the development of a new generation of tolerogenic drugs that will "turn off" selected parts of the immune system, leaving the disease-fighting capabilities intact.

Our efforts to modulate T cell activation have centered on understanding and altering the positive signals delivered by the antigen-specific T cell receptor and secondary, so-called co-stimulatory signals, or engaging the negative regulatory events such as CTLA-4 and PD-1 that control T cell signal transduction. The studies focus on the blockade of co-stimulatory molecules, such as CD28 and CD40L, which are essential for a productive T cell response. Blockade of CD28 interactions with its ligands, B7-1 and B7-2, induces long term tolerance in several different animal models. However, the precise biological basis for tolerance induction remains unclear. We have used soluble receptor antagonists, monoclonal antibodies and animals deficient in individual members of the CD28/B7 pathway to define their individual roles in transplant rejection and autoimmunity. We have shown that CD28 co-stimulation blockade alters cell growth and survival, the differentiation state of the T cells and their ability to migrate into the inflammatory site. In critical studies, we showed that administration of a CD28 antagonist induces long-term, antigen-specific unresponsiveness in vivo in pancreatic islet transplant models in both mice and monkeys and regulates the progression of autoimmune diseases in mice.

We have demonstrated that the CD28 pathway controls CD4+CD25+ regulatory T cells that control autoimmunity thus implicating CD28 in both the pathogenic and protective immune responses. Recent studies have emphasized the limitation of co-stimulation blockade in the autoimmune setting. T cells in animals experiencing chronic inflammation (such as active autoimmunity) appear to bypass the need for co-stimulation to promote T cell activity and, in fact, co-stimulation blockade disrupts essential regulatory pathways resulting in the exacerbation of immunity in some settings. These studies have led to identification of a critical role for CD4+CD25+ cells in the regulation of autoimmune diabetes and subsequent research efforts using gene array to identify novel genes that control regulatory T cell function. Moreover, this work has led to the examination of a number of other co-stimulatory molecules (4-1BB, PD-1, ICOS and CD40L) in the development and progression of diabetes. Current efforts suggest that combination therapy may be most effective in blocking diabetes in the NOD mouse model. Finally, we have begun to study Tregs in humans with the goal of in vivo therapy with expanded cells. The animal data suggests that expanded antigen-specific Tregs can reverse diabetes in NOD mice.

Additional efforts in the lab have yielded insights into the function of the CD28 homologue, CTLA-4. Our laboratory was the first to demonstrate that T cell signaling via this molecule down-regulates T cell proliferation and cytokine production. Blockade of this molecule on activated T cells promotes immune responses including enhancing tumor remission. It is now clear that CTLA-4 engagement is essential in the development and maintenance of T cell tolerance in the autoimmune setting. We have begun to elucidate the biochemical basis of this regulatory signal through its interaction with the TCR complex.

Finally, we have developed a novel, genetically engineered "human", form of an anti-CD3 mAb for use in solid organ transplantation and autoimmunity. Unlike the parent drug, OKT3, the mutagenized form has none of the toxic side effects and can be given repeatedly. We have shown in animal models that these monoclonal antibodies can induce T cells into a state of unresponsiveness that leads to long term T cell tolerance to foreign antigens. This tolerant state is related to altered signaling events in the T cells as a consequence of differential protein phosphorylation and cytokine production. More recently, we have shown that treatment of mice with these reagents can induce profound apoptosis that reduces clonal size and promotes tolerance. In human studies, we have shown that a humanized OKT3 g 1 (Ala-Ala) has been used in multiple clinical trials including new onset Type 1 Diabetes, Psoriatic Arthritis, Islet and Kidney Transplantation.

Thus, in summary, my lab has been involved in efforts to modify transplantation and autoimmune responses and understand the underlying mechanisms of T cell recognition of foreign antigens. Using this information we hope to develop novel tolerogenic therapies that can be tested in man.