The Mackall laboratory has a primary focus on the study of T cell homeostasis as it relates to lymphopenia and immune reconstitution. The goal of this work is to learn how to exploit the alterations in immune reactivity which occur during lymphopenia to enhance antitumor immunity and to identify new therapies which can enhance T cell regeneration. Both mouse and human immunology are simultaneously studied in an iterative manner using genetically engineered mice, murine allogeneic transplantation models, studies of humans rendered lymphopenic by cytotoxic chemotherapy for cancer and studies of humans following allogeneic stem cell transplantation. Our previous work identified that IL7 is a central modulator of T cell homeostasis (2001, Fry et al., Blood 97:2983), that therapy with IL7 modulates thymic-dependent and thymic-independent T cell immune reconstitution (2001, Mackall et al. Blood, 97:1491) and that effects of IL7 on peripheral T cell homeostasis can restore immunity in athymic T cell depleted hosts (2003, Fry et al., Blood 101:2294 and 2004, Moniuszko et al., J Virol 104:1419). These findings served as a basis for a Phase I clinical trial of rhIL7 in humans which is currently underway and which has confirmed a critical role for IL7 in modulating T cell number in humans. Beyond this, 8 subprojects are underway or have been recently completed within the laboratory which seek to advance our understanding of the biology and therapy for T cell depletion. 1) We have now completed a series of studies which demonstrate that IL7 is a potent adjuvant when used in the context of a dendritic cell based vaccine. This work utilized a mouse dendritic cell vaccine model to immunize toward the minor histocompatibility antigen HY, for which both immunodominant and subdominant epitopes have been characterized. We compared the efficacy of rhIL2, rhIL7, or rhIL7+rhI15 in augmenting T cell responses in this system by monitoring tetramer binding cells, IFN-gamma production via Elispot and rejection of a tumor which expressed HY. We observed potent increases in CD8+ reactive HY specific cells with both rhIL7 and rhIL15 but not with rhIL2. Both immunodominant and subdominant populations increased, but the effects on subdominant responses were most striking. IL7 also increased CD4 effectors but IL15 and IL2 did not. Both IL7 and IL15 increased the size of the memory cell pool generated and remarkably, even a short course of IL7 or IL15 administered at the time of immunization led to long-term enhancement in the viability of the CD8+ memory pool. This resulted from a substantial improvement in the long term survival of memory cells generated under the influence of IL7, suggesting that provision of this cytokine at the time of initial antigen encounter may result in long term changes to the health of the resultant memory cell pool. These results were published in a manuscript entitled, """"""""Adjuvant IL7 or IL15 Overcomes Immunodominance and Improves Survival of the Memory Cell Pool"""""""", Melchionda et al., Journal of Clinical Investigation, 2005, 115:1177-1187. This represents the first evidence that IL7 is a potent vaccine adjuvant which has a remarkable capacity to augment subdominant immune responses and will no doubt serve as the basis for subsequent clinical studies of IL7 in the context of tumor vaccines. 2) During the past year, we also published a report which was the first to identify flt3 ligand as an immunorestorative agent (Flt3 Ligand enhances thymic dependent and thymic-independent immune reconstitution. Fry et al., Blood, 2004, 104:2794-2800). Using murine models of T cell depletion, we discovered that homeostatic peripheral expansion (which serves as the primary pathway for T cell regeneration in athymic hosts) requires the presentation of antigen by professional antigen presenting cells (APCs).
| 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 |
| 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 |
| 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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