Directing T Cell Responses during Immune Reconstitution

Clinical Sciences

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Abstract

A primary focus of our laboratory is investigation of the biology of T cell regeneration and the identification of new approaches to enhance T cell regeneration and to direct T cell responses toward tumor antigens during the period of immune reconstitution. Our methods involve modeling in mice, studies in non-human primates and studies involving clinical samples derived from patients with T cell depletion. Much of the work in the past year has utilized mouse models of T cell depletion. Through this, we have investigated mechanisms for enhancing T cell regeneration in thymic deficient mice. We have shown that recovery of stringent immune responses (HY skin graft rejection) occurs if only 10% of the T cell repertoire is supplied to a T cell depleted host by the transfer of normal mature T cells. Such a small inocula implies that much redundancy occurs within the immune system and represents a new discovery. We also learned that one could transfer as little as 1% of the T cell repertoire with a T cell active cytokine, IL-7, and similarly restore stringent immune responses. Such results were surprising because prior to this work, IL-7 was thought of as a cytokine which was important for early T cell development, but its effects on mature T cells were not generally believed to be of primary importance (Fry TJ, Christensen BL, Komschlies KL, Gress RE and Mackall CL. IL-7 restores immunity in athymic T cell depleted hosts. Blood. 2001;97:1525-1533) (Mackall CL, Fry TJ, Bare C, Morgan P, Gailbraith A and Gress RE. IL-7 increases both thymic-dependent and thymic-independent T cell regeneration after BMT. Blood. 2001;97:1491-1497.). Simultaneously, we hypothesized that if therapeutic doses of IL-7 were able to potently restore immune responses in T cell depleted hosts, it was possible that in the normal situation, endogenous levels of IL-7 serve to enhance immune competence and contribute to the restoration of T cell homeostasis following T cell depletion. Indeed, several features of IL-7 treated mice resemble T cell depleted hosts. Thus, we investigated serum IL-7 levels in clinical cohorts of patients with T cell depletion. We observed that there was a dramatic inverse correlation between serum IL-7 and CD4 count in HIV infection, following cancer chemotherapy and in a rare disease termed idiopathic CD4 lymphopenia (Fry TJ, Connick E, Falloon J, Lederman MM, Liewehr DJ, Spritzler J, Steinberg SM, Wood LV, Yarchoan R, Zuckerman J, Landay A and Mackall CL. A potential role for IL-7 in T cell homeostasis. Blood, 2001; 97:2983-2990). These were the first insights to implicate IL-7 as a possible regulator of T cell homeostasis in humans (Fry TJ and Mackall CL, Interleukin-7: Master Regulator of T Cell Homeostasis?, Trends in Immunology, In Press, 2001). Because of these findings in both mouse models and clinical samples, we have been very actively attempting to develop IL-7 as a clinical agent which could be used to improve immunity following T cell depletion. To this end, we are engaged in trials of IL-7 administration to non-human primates through collaborations with the Monoclonal Antibody and Recombinant Protein Facility in Frederick, MD and Sanofi, Inc. in Paris, France through an MTA/CRADA with the NCI. We are hopeful that these studies will eventually lead to clinical trials of IL-7 as a new immunorestorative agent. In addition, we have identified two new agents in the past year with the potential for clinical application as immunorestorative agents. The first, flt3 ligand is known to enhance dendritic cell development. However, through our murine models of T cell depletion, we have now observed that it also enhances both thymic-dependent and thymic-independent T cell regeneration (Fry/Sinha, ASH, 2001). Secondly, we have observed that the HIV protease inhibitor, Indinavir, is active as an immunorestorative agent in mouse models, even in the absence of HIV infection. We are also engaged in two murine tumor models which will serve to answer questions regarding the ability of immune restoration to prevent recurrence of cancer. In the first, we are using a bladder tumor for which a unique tumor antigen has been defined. This antigen, termed HY, is the male associated minor histocomability antigen which is the antigen we have studied extensively in skin graft rejection models (above). We will now determine whether we can similarly enhance resistance to tumor recurrence in T cell depleted hosts using IL-7. Secondly, we are using a mouse model of osteosarcoma. In this model, the tumor is implanted into the extremity and the animal subsequently receives an amputation after tumor growth. We then attempt to modulate immune reconstitution and evaluate the effects on tumor recurrence. This model is very similar to the clinical scenario of osteosarcoma which we observe in our patients. We have made the surprising observation that non-specific immune reconstitution, in the absence of any specific tumor vaccine, is capable of preventing tumor recurrence following amputation (Melchionda et al, submitted to ASH 2001). Furthermore, we find no evidence that lymphocytes present during the phase of primary tumor growth are tolerized to the tumor antigens. These studies imply that therapies aimed at restoring general immunity in cancer patients may contribute to prevent tumor recurrence and have important implications for clinical oncology. AIDS Related 100%