The objectives of this project are to study the biology of T cell regeneration and to develop therapeutic approaches which could be used in T cell depleted hosts to improve overall host immunocompetence and to direct T cell responses toward tumor-specific antigens in the setting of minimal residual neoplastic disease. Using a murine model of HY skin graft rejection, following T cell depletion, we have shown that thymectomized mice which have undergone immune reconstitution via peripheral expansion are unable to reject HY disparate skin grafts while hosts reconstituted via thymic-dependent pathways reject grafts normally. Rejection is accomplished in thymectomized mice if sufficient numbers of T cells are provided which we have shown requires approximately 10% of the normal T cell repertoire. In these experiments, we have also shown that IL-7 potently enhances thymic-independent T cell regeneration and that IL-7 therapy restores the capacity to reject HY disparate grafts in thymectomized hosts reconstituted with insufficient T cell numbers. Mechanistically, this appears to be related, at least in part, to IL-7?s ability to inhibit programmed cell death since inhibition of programmed cell death (PCD) by the use of bcl-2 transgenic T cell inocula also enhances immune competence in this model. Therefore, these results suggest that PCD may serve to limit host immune competence during peripheral expansion and raise the possibility that modulation of PCD in vivo may serve as a useful approach for enhancing immune competence in thymic-deficient TCD hosts. This model has also emphasized the critical role of IL-7 in modulating the process of peripheral expansion in vivo. Based upon these results, we have hypothesized that endogenous IL-7 production could contribute to T cell homeostasis by enhancing the process of peripheral expansion in the setting of T cell depletion. In order to test this hypothesis, we sought to evaluate serum IL-7 levels in children with T cell depletion due to HIV infection. We have observed a striking inverse correlation between serum IL-7 levels and T cell counts in children with HIV associated CD4+ depletion. Statistically, the serum IL-7 levels appear to be related to both CD4+ and CD8+ T cell counts, but not B cell counts. Current work is underway to address whether similar relationships exist in adults with T cell depletion and in T cell depletion related to cytotoxic therapy. These studies may serve to identify a new role for IL-7 in maintenance of T cell homeostasis.With regard to thymic-dependent pathways of T cell regeneration, we are currently investigating the relative importance of age- or disease-associated thymic dysfunction in limiting T cell receptor repertoire diversity following T cell depletion in humans. In order to evaluate the ability of low level thymic function to diversify the T cell receptor (TCR) repertoire over time in humans, current work is focused upon evaluation of TCR repertoire diversity in a series of pediatric patients treated with highly active antiretroviral therapy for HIV infection. We have hypothesized that even suboptimal thymopoiesis in this patient population may lead to diversification of the TCR repertoire over time. In an attempt to measure such changes in TCR diversity, we have developed a semi-quantitative approach using complementarity determining region 3 (CDR3) size analysis of serially diluted purified CD4+ T cells. Interestingly, preliminary results using this approach in normal individuals have shown significant age related changes in T cell receptor repertoire diversity. Whereas cord blood shows a diverse repertoire with as few as 10e5 input CD4 cells, young adults do not show a diverse repertoire until 5 x 10e5 input CD4 cells are utilized. Older adults (40-50 years) do not show a diverse repertoire until 1 x 10e6 input CD4+ T cells are utilized. These results suggest that measurable declines in TCR repertoire diversity occur throughout the normal human lifespan. With regard to children treated with highly active antiretroviral therapy, we have observed significantly reduced TCR repertoire diversity in children with CD4+ T cell counts <200 cells/mcl. In contrast, preliminary results in children with higher CD4+ T cell counts (e.g. >400 cells/mcl) reveal essentially normal TCR repertoire diversity. We have also used this approach to compare TCR repertoire diversity in CD45RA+ vs. CD45RO+ CD4+ T cells from patients with HIV infection. Thus far, no significant differences in repertoire diversity have been observed. Future plans involve the use of this technique to monitor changes in TCR repertoire diversity in cancer patients treated with immunorestorative therapies in the context of our ongoing clinical trials. AIDS RELATED 100%
| Guimond, Martin; Veenstra, Rachelle G; Grindler, David J et al. (2009) Interleukin 7 signaling in dendritic cells regulates the homeostatic proliferation and niche size of CD4+ T cells. Nat Immunol 10:149-57 |
| Capitini, Christian M; Cooper, Laurence J N; Egeler, R Maarten et al. (2009) Highlights of the First International ""Immunotherapy in Pediatric Oncology: Progress and Challenges"" Meeting. J Pediatr Hematol Oncol 31:227-44 |
| Fluur, Caroline; De Milito, Angelo; Fry, Terry J et al. (2007) Potential role for IL-7 in Fas-mediated T cell apoptosis during HIV infection. J Immunol 178:5340-50 |
| Hazra, Rohan; Jankelevich, Shirley; Mackall, Crystal L et al. (2007) Immunologic, virologic, and neuropsychologic responses in human immunodeficiency virus-infected children receiving their first highly active antiretroviral therapy regimen. Viral Immunol 20:131-41 |
| Merchant, Melinda S; Melchionda, Fraia; Sinha, Manoj et al. (2007) Immune reconstitution prevents metastatic recurrence of murine osteosarcoma. Cancer Immunol Immunother 56:1037-46 |
| Crooks, Gay M; Weinberg, Kenneth; Mackall, Crystal (2006) Immune reconstitution: from stem cells to lymphocytes. Biol Blood Marrow Transplant 12:42-6 |
| Lucas, Philip J; Kim, Seong-Jin; Mackall, Crystal L et al. (2006) Dysregulation of IL-15-mediated T-cell homeostasis in TGF-beta dominant-negative receptor transgenic mice. Blood 108:2789-95 |
| Krupica Jr, Tom; Fry, Terry J; Mackall, Crystal L (2006) Autoimmunity during lymphopenia: a two-hit model. Clin Immunol 120:121-8 |
| Snyder, Kristen M; Mackall, Crystal L; Fry, Terry J (2006) IL-7 in allogeneic transplant: clinical promise and potential pitfalls. Leuk Lymphoma 47:1222-8 |
| Guimond, Martin; Fry, Terry J; Mackall, Crystal L (2005) Cytokine signals in T-cell homeostasis. J Immunother (1997) 28:289-94 |
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