This laboratory is engaged in studies of bone marrow transplantation (BMT) directed toward two clinical applications: 1) the treatment of hematologic malignancies; and 2) the induction of specific transplantation tolerance. Toward the first goal, we are attempting to understand the basis for our observation that, under certain circumstances, graft-vs-host (GVH) alloresponses can remain within the lymphohematopoietic system where they mediate graft-vs-leukemia (GVL) responses, without accumulating in the parenchymal target tissues where GVHD occurs. We are investigating the basis of this behavior in mouse models and have recently demonstrated a critical role of GVHD target tissue inflammation, such as that induced by TLR stimuli, in converting a beneficial “lymphohematopoietic GVH response” to GVHD. This control by inflammation is elicited at the level of access of activated GVH-reactive T cells to the GVHD target tissues. We are analyzing clinical material from a clinical bone marrow transplantation trial that is based on this approach to separating GVL from GVHD. Based on some surprising results obtained in one of these trials, we hypothesized that rejection of donor marrow in recipients prepared with less toxic, non-myeloablative regimens, might lead to anti-tumor responses. We have demonstrated in the mouse model that this is indeed the case, and that this effect is associated with the generation of tumor-specific cytotoxic responses. Studies are ongoing to understand the complex pathway, probably involving the indirect alloresponse, that leads to this phenomenon, which provides a potential means of achieving anti-tumor responses without the risk of GVHD.
Toward the second goal, we have focused on the development of non-toxic, non-myeloablative conditioning regimens using mAbs or costimulatory blockade to eliminate host resistance to engraftment of allogeneic and xenogeneic bone marrow cells and allow creation of a mixed chimeric state, and hence the induction of specific transplantation tolerance. The clinical use of such approaches could obviate the need for risky chronic immunosuppressive therapy. We are attempting to understand the mechanisms of peripheral tolerance of CD4 and CD8 T cells that encounter donor antigens on bone marrow cells in the presence of costimulatory blockade. We have obtained evidence that both activation-induced cell death and passive cell death lead to early deletion of these donor-reactive cells. Anergy precedes the death of peripheral donor-reactive T cells, and studies are in progress to understand these phenomena in more detail. We have begun clinical studies of the mixed chimerism approach to induce renal allograft tolerance, and our laboratory is actively investigating the mechanisms involved in tolerance in this unique cohort of patients.
The induction of tolerance to xenogeneic donors could overcome the organ shortage that currently limits the field of solid organ transplantation. We have developed a method of inducing xenograft tolerance that involves replacing the recipient mouse thymus with a xenogeneic pig thymus. Host CD4 T cells develop normally in these grafts. These cells are specifically tolerant of pig tissue, and mount powerful host MHC-restricted immune responses, despite being positively selected only by porcine MHC. However, studies are underway to understand the basis of abnormalities in the function of regulatory cells developing in xenogeneic thymus tissue. Porcine thymic tissue generates human T cells in immunodeficient mice, and these T cells are also specifically tolerant of the porcine donor and demonstrate a normal TCR repertoire. We have combined this approach with a novel, multilineage reconstituted humanized mouse model, to test the ability of porcine thymus grafts to induce functional human regulatory cells and to assess the ability of such human T cells to undergo normal lymphopenia-driven expansion. We have recently shown that mixed hematopoietic chimerism can be used to induce tolerance among natural antibody-producing B cells that produce anti-a1,3 Gal natural antibodies that are of critical importance in xenotransplantation. We are currently performing studies to determine the mechanism by which pre-existing and newly formed anti-a1,3 Gal-producing B cells are tolerized in mixed chimeras. We have identified a unique CD5-negative, Mac1-negative splenic B cell subpopulation as the major source of anti-Gal and all other IgM natural antibodies, and we are analyzing the lineage relationship between these cells and more classical peritoneal cavity B-1 cells. We are investigating the mechanisms of anergy that lead to tolerance of pre-existing Gal-reactive B cells in mixed chimeras. Long-term tolerance appears to involve mainly deletion and/or receptor editing of newly developing B cells.
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Papers & Publications:
1. R. Chakraverty, H. S. Eom, J. Sachs, J. Buchli, P. Cotter, R. Hsu, G. Zhao, and M. Sykes. Host MHC Class II+ antigen-presenting cells and CD4 cells are required for CD8-mediated graft-versus-leukemia responses following delayed donor leukocyte infusions. Blood. 2006; 108(6):2106-2113.
2. R. Chakraverty, D. Cote, J. Buchli, P. Cotter, R. Hsu, G. Zhao, T. Sachs, C. Psitilides, R. Bronson, T. Means, C. Lin, and M. Sykes. An inflammatory checkpoint regulates recruitment of graft-versus-host-reactive T cells to peripheral tissues. J. Exp. Med. 2006; 203(8):2021-2031.
3. Wekerle T, Sayegh MH, Hill J, Zhao Y, Chandraker A, Swenson KG, Zhao G and Sykes, M. Extrathymic T cell deletion and allogeneic stem cell engraftment induced with costimulatory blockade is followed by central T cell tolerance. J.Exp. Med. 1998, 187:2037-2044.
4. Fehr T, Takeuchi Y, Kurtz J, Wekerle T, Sykes M. Early regulation of CD8 T cell alloreactivity by CD4(+)CD25(- )T cells in recipients of anti-CD154 antibody and allogeneic BMT is followed by rapid peripheral deletion of donor-reactive CD8(+) T cells, precluding a role for sustained regulation. Eur. J. Immunol. 2005;35:(9)2679-2690.
5. Fudaba Y, Spitzer TR, Shaffer JM, Kawai T, Fehr T, Delmonico FL, Preffer FI, Tolkoff-Rubin, Dey BR, Saidman SL, Kraus A, Bonnefoix T, McAfee S, Power K, Kattelman K, Colvin RB, Sachs DH, Cosimi AB Sykes M. Myeloma responses and tolerance following combined kidney and non-myeloablative marrow transplantation in vivo and in vitro analyses. Am. J. Transplant. 2006; 6:2121-2133 |
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