Biology and Therapy of Lymphopenia

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We previously demonstrated that thymic function is a rate limiting factor in reconstitution of T cells following lymphocyte depletion. Thymic function is inhibited by age associated decreases as well as the toxicity of therapies administered to patients undergoing bone marrow transplantation and cancer therapy. The first major accomplishment of this project in FY2010 was the publication of a report demonstrating that non-toxic, a small molecule tyrosine kinase inhibitor (sunitinib) could enhance thymic and bone marrow engraftment as a single agent following bone marrow transplantation (Fewkes et al, Blood, 2010). This is notable since this agent does not function by killing thymic stroma or progenitor cells, but rather transiently starves early thymic progenitors of critical nutrients, but leaving overall long term function intact. This holds promise in the development newer, less toxic approaches to bone marrow transplantation and cell based therapies, which as a result would lead to enhanced immune reconstitution in these settings. A second major accomplishment of this project in FY11 was publication of the results of our first clinical trial of rhIL7 in humans, which demonstrated potent effects on early B cells and documented prolonged T1/2 of this cytokine agent. These results were surprising as previous work had demonstrated cytokines to be very short lived in vivo (Sportes et al, Clin Can Res 2010). The results also clearly documented the potent immunorestorative effects of rhIL7 and demonstrated minimal toxicity, thus setting the stage for use of this agent in a variety of settings aimed at enhancing immune reconstitution, vaccine responses and antiviral responses in the setting of chronic viral infection. Indeed, based upon the results of this study, there are currently over 20 studies worldwide underway utilizing IL7 as an immunomodulator and this agent holds great promise for eventual approval for use in a variety of clinical settings. A third accomplishment of this project during FY11 was publication of a summary article detailing the promising of interleukin-7 for clinical use in the premier immunology review journal worldwide (Mackall et al, Nat Rev Immunology). A fourth accomplishment of this project during FY11 has been to extend work previously published by this laboratory in 2009 (Guimond et al, Nat Imm) where we demonstrated the importance of IL7 signaling on non-T cells in regulating CD4+ T cell homesotasis. In these as yet unpublished studes, we have observed that animals deficient in IL7R expression on non-T cells show paradoxically increased T cell proliferation to self antigens and tumors antigens and these observations could potentially be exploited for antitumor effects in clinical settings. They may also shed light on susceptibility to autoimmune disease and these studies are ongoing. The fifth accomplishment of this project for the FY2011 was completion of studies demonstrating an important role for soluble IL7 receptor in modulating bioactivity of IL7. We initiated a project studying the biology of IL7 receptor because polymorphisms in this gene have been linked to differential susceptibility to multiple sclerosis. Despite this, there was essentially no understanding of the biology surrounding soluble IL7R and therefore this genetic finding could not be placed in a biological context. Through these studies, we found that when soluble IL7R is present, very short term "high burst" signaling of IL7 is diminished but over the longer term (e.g. days) there is diminished IL7 consumption and as a result, over the long term there is increased biologic activity of IL7. These results provide fundamental insights into the important role that IL7R plays in modulating IL7 bioactivity in vivo, provide further insight how genetic polymorphisms increase susceptibility to multiple sclerosis when increased levels of soluble IL7R are present and could be used to enhance the effectiveness of IL7 when used as a therapeutic agent.