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There are currently three areas of research in the Latchman laboratory:
The prevalence of systemic lupus erythematosus (SLE) worldwide has been estimated to be 40 in 100,000 individuals and has given impetus to investigate novel therapeutic approaches to the treatment of the disease. The underlying immunological and genetic mechanisms of the disease are still unclear but many studies have highlighted the breakdown in B and T cell tolerance. Studies of autoimmune–prone mouse strains have begun to identify genetic loci that may contribute to the initiation and progression of this disease. Of interest, is the Sle1b susceptible generegion, which contains members of the CD2 superfamily including CD48, CD244 (2B4), CD84, CD150 (SLAM), CD299 (Ly-9) and Ly-108 molecules. The presence of CD2 superfamily members within the Sle1b region raises the question of whether one or more of these family members have a role in SLE. Utilizing mouse models, we are investigating the role of the CD48 pathway in T, B and dendritic cell function. Our recent studies have implied an important role for CD48 in tolerance and therefore we are studying how this pathway participates in the development of autoimmune diseases such as systemic lupus erythematosus. These studies will provide key insights into the role of CD48 interactions in regulating T and B cell tolerance and may provide important targets for therapeutic interventions in SLE.
The B7-CD28/CTLA-4 superfamily has grown recently and a new inhibitory pathway involving PD-1 and PD-1 ligands (PD-L1 and PD-L2) has been defined. PD-L1 and PD-L2 are expressed on professional APCs as well on a variety of tumor cell lines. Engagement of PD-1 by its ligands can lead to inhibition of T cell proliferation and cytokine production. The expression of PD-L1 and PD-L2 on tumor cell lines suggests a potential mechanism by which tumors may evade an immunological response. These findings have lead us to investigate whether the expression PD-1 ligands on tumors attenuates anti-tumor responses. To study the functions of PD-1 ligands in T cell regulation, we are using PD-1 ligand deficient mice. We are investigating the role of these ligands in controlling T and NKT cell responses using transgenic approaches and tumor models. Our studies thus far suggest that blockade of the interaction of PD-1 ligands and their receptor PD-1 may provide a means to enhance anti-tumor immunity.
Several studies have shown that repeated platelet transfusions might lead to alloimmunization due to HLA antigens expressed on contaminating leukocytes. Recipients may develop refractoriness to platelet transfusion from random donors and may require some degree of HLA class II matching between donor and recipient. As finding HLA matched donors is often difficult, leukoreduction of transfused blood products has been used to decrease alloimmunization rates. Human studies and animal models have demonstrated that leukoreduction decreases alloimmunization rates but does not eliminate the problem. In collaboration with Drs Slichter and Nelson, we are utilizing a mouse model of allogeneic platelet transfusion together with knockout mice (i.e. .B, T and NKT) as donors to identify the cells that are involved in decreasing or increasing alloimmunization rates. In addition, we are studying the cells that are important in tolerance induction during platelet transfusion. Ultimately, identification of alloimmunizing and tolerizing cells may provide a better plan for improving leukoreduction strategies and reduce or eliminate the rate of alloimmunization rates after multiple platelet transfusions.
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