In this project, we have found that immune T cells that are expanded ex vivo in the presence of rapamycin can develop resistance to rapamycin provided that necessary co-stimulation and cytokine signals are provided. Importantly, we have shown that a great variety of functional T cell subsets can be generated in rapamycin, including the Th1, Th2, Tc1, Tc2, and regulatory T cell subsets. Of significance, we have found that T cells that acquire rapamycin-resistance also attain an apoptosis resistance phenotype;this biology has functional significance because upon adoptive T cell transfer, such rapamycin- and apoptosis-resistant T cell have increased in vivo survival and therefore mediate more potent immune T cell reactions relative to control T cells. We have recently found that rapamycin causes polarized T cells to undergo a process known as autophagy;the anti-apoptotic phenotype of rapamycin-generated T cells is dependent upon autophagy. We have observed that this biology occurs with both murine T cells and human T cells. Given this understanding, we have initiated pilot clinical trials at the NIH Clinical Center using rapamycin-resistant T cells for the therapy of leukemia, lymphoma, and renal cell carcinoma.
|Castiello, Luciano; Mossoba, Miriam; Viterbo, Antonella et al. (2013) Differential gene expression profile of first-generation and second-generation rapamycin-resistant allogeneic T cells. Cytotherapy 15:598-609|
|Fowler, Daniel H; Mossoba, Miriam E; Steinberg, Seth M et al. (2013) Phase 2 clinical trial of rapamycin-resistant donor CD4+ Th2/Th1 (T-Rapa) cells after low-intensity allogeneic hematopoietic cell transplantation. Blood 121:2864-74|
|Granville, Courtney A; Memmott, Regan M; Balogh, Andria et al. (2009) A central role for Foxp3+ regulatory T cells in K-Ras-driven lung tumorigenesis. PLoS One 4:e5061|
|Mariotti, Jacopo; Foley, Jason; Jung, Unsu et al. (2008) Ex vivo rapamycin generates apoptosis-resistant donor Th2 cells that persist in vivo and prevent hemopoietic stem cell graft rejection. J Immunol 180:89-105|
|Svirshchevskaya, Elena V; Mariotti, Jacopo; Wright, Mollie H et al. (2008) Rapamycin delays growth of Wnt-1 tumors in spite of suppression of host immunity. BMC Cancer 8:176|
|Foley, Jason E; Mariotti, Jacopo; Ryan, Kaitlyn et al. (2008) Th2 cell therapy of established acute graft-versus-host disease requires IL-4 and IL-10 and is abrogated by IL-2 or host-type antigen-presenting cells. Biol Blood Marrow Transplant 14:959-72|
|Mariotti, Jacopo; Foley, Jason; Ryan, Kaitlyn et al. (2008) Graft rejection as a Th1-type process amenable to regulation by donor Th2-type cells through an IL-4/STAT6 pathway. Blood :|