The broader, long-term objectives of this proposal are to dissect the mechanisms governing alloimmune responses of adoptively transferred donor T cells after their administration to established allogeneic chimeras and to use this data to develop clinically translatable strategies to augment anti- tumor immunity. Our preliminary studies suggest that after MHC-matched allografting, host-derived dendritic cells (DCs) persist in the skin, despite the apparent full donor DC chimerism in the blood and ongoing graft-versus-leukemia (GVL) responses. Furthermore, we found that adoptive transfer of donor T cells to allogeneic MHC-matched chimeras, in which all blood DCs are of donor origin, can lead to graft-versus-host (GVH) reactivity toward residual host skin DCs. Interestingly, DLI administration to chimeras that have been topically treated with the Toll-like receptor (TLR)7 ligand, imiquimod, not only augmented the DLI-mediated GVH reactivity, but also the GVL response. These responses, if combined with tumor vaccination, resulted in the ability of treated animals to exhibit an anamnestic response to tumor re-challenge. Accordingly, the central hypothesis of this proposal is that donor T cell?host skin DC interactions play a principal role in the induction of an alloimmune response in complete donor chimeras post-transplant;and, moreover, that the outcome of these responses can be manipulated in vivo with defined molecular ligands and tumor vaccines to result in long-lasting anti-tumor immunity. To investigate this hypothesis, the following specific aims are proposed: 1) To characterize the cellular and molecular mechanisms governing T cell?DC interactions post MHC-matched allografting. These studies will determine the roles of host and donor DCs on the DLI-mediated GVH and GVL reactivities and characterize the role of TLR-mediated signaling;and 2) To determine the role of T cell?DC interactions on the vaccine-induced responses after allografting. These studies will examine the functional significance of residual host skin DCs and donor blood DCs on the induction of antigen-specific T cells and vaccine-induced immunity. The immediate goal of the studies described in this proposal is to develop novel therapeutic strategies that may lead to improved anti- tumor immunity;the long-term goal is to translate these findings to the clinic. Scope of the work: The central hypothesis behind this proposal is that interactions between donor T cells and residual host skin DCs play a principal role in the induction of alloimmune responses in complete donor chimeras post-transplant and that outcome of these responses can be manipulated in vivo with defined molecular ligands and tumor vaccine resulting in long-lasting anti-tumor immunity. Thus, the goal of the proposed study is to dissect the mechanisms governing alloimmune responses in established MHC- matched allogeneic chimeras and to use this data to develop clinically translatable strategies to augment anti-tumor immunity.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA122779-05
Application #
8208131
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Yovandich, Jason L
Project Start
2008-03-01
Project End
2013-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
5
Fiscal Year
2012
Total Cost
$295,461
Indirect Cost
$115,302
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Dodd-O, Jeffrey M; Ganguly, Sudipto; Vulic, Ante et al. (2016) Induction of MHC-mismatched Mouse Lung Allograft Acceptance with Combined Donor Bone Marrow: Lung Transplant using a 12-Hour Nonmyeloablative Conditioning Regimen. Transplantation :
Flynn, Ryan; Paz, Katelyn; Du, Jing et al. (2016) Targeted Rho-associated kinase 2 inhibition suppresses murine and human chronic GVHD through a Stat3-dependent mechanism. Blood 127:2144-54
Dodd-O, Jeffrey M; Ganguly, Sudipto; Vulic, Ante et al. (2016) Induction of Major Histocompatibility Complex-mismatched Mouse Lung Allograft Acceptance With Combined Donor Bone Marrow: Lung Transplant Using a 12-Hour Nonmyeloablative Conditioning Regimen. Transplantation 100:e140-e146
Ganguly, Sudipto; Ross, Duncan B; Panoskaltsis-Mortari, Angela et al. (2014) Donor CD4+ Foxp3+ regulatory T cells are necessary for posttransplantation cyclophosphamide-mediated protection against GVHD in mice. Blood 124:2131-41
Kanakry, Christopher G; Ganguly, Sudipto; Zahurak, Marianna et al. (2013) Aldehyde dehydrogenase expression drives human regulatory T cell resistance to posttransplantation cyclophosphamide. Sci Transl Med 5:211ra157
Luznik, Leo; O'Donnell, Paul V; Fuchs, Ephraim J (2012) Post-transplantation cyclophosphamide for tolerance induction in HLA-haploidentical bone marrow transplantation. Semin Oncol 39:683-93
Luznik, Leo; Jones, Richard J; Fuchs, Ephraim J (2010) High-dose cyclophosphamide for graft-versus-host disease prevention. Curr Opin Hematol 17:493-9
Radojcic, Vedran; Pletneva, Maria A; Yen, Hung-Rong et al. (2010) STAT3 signaling in CD4+ T cells is critical for the pathogenesis of chronic sclerodermatous graft-versus-host disease in a murine model. J Immunol 184:764-74
Radojcic, Vedran; Bezak, Karl B; Skarica, Mario et al. (2010) Cyclophosphamide resets dendritic cell homeostasis and enhances antitumor immunity through effects that extend beyond regulatory T cell elimination. Cancer Immunol Immunother 59:137-48