The absence of a suitably HLA-matched donor precludes hematopoietic cell transplantation (HCT) in many patients, as the risks of graft-versus-host disease (GVHD) and rejection are formidable when extensive HLA barriers are transgressed. HLA-mismatched HCT without rejection or severe GVHD would make this treatment available to patients lacking a matched donor, and could maximize graft-versus-tumor (GVT) effects. The toxicity of allogeneic HCT can be diminished using non-myeloablative conditioning. The major goal of this Program Project is to develop non-myeloablative approaches to HLA-mismatched HCT, while minimizing GVHD and exploiting the potent GVT effect of anti-MHC GVH alloreactivity. Two major strategies will be explored in animal models, and a third will be characterized mechanistically. Nonmyeloablative allogeneic HCT that includes T cell depletion of the recipient and donor inoculum can lead to mixed hematopoietic chimerism across extensive MHC barriers without GVHD. When donor lymphocyte infusions (DLI) are administered to established murine mixed chimeras, the GVH alloresponse associated with subsequent DLI leads to powerful GVT effects without GVHD. Recipient-derived professional antigenpresenting cells (APC) in mixed chimeras maximize GVH alloresponses and thereby maximize GVT, while GVHD, a disease of epithelial target tissues, is avoided. We have taken these observations from mice to a unique large animal (pig) model and into clinical trials for the treatment of leukemias and lymphomas. Two of the Projects (Project 1 in mice, Project 3 in large animals) focus on the administration of delayed DLI to mixed allogeneic chimeras prepared with non-myeloablative conditioning that includes T cell-depleting mAbs, in order to achieve maximal GVL effects without GVHD. The goals of expanding donor hematopoietic stem cells (HSC) ex vivo and in vivo and improving immune recovery in Project 4 will ultimately be applicable to the clinical application of this approach, since large numbers of purified (T cell-depleted) donor HSC may be required to achieve engraftment across extensive HLA barriers. Project 4 includes an initial clinical evaluation of the ability of PTH to expand the numbers of mobilized HSC in patients failing conventional mobilization treatment. Large animal studies to evaluate the use of PTH to enhance allogeneic HSC engraftment (Project 3) will provide a critical bridge between the pre-clinical and clinical applications of these strategies (Project 4). Like Project 1, Project 2 involves confinement of the GVH alloresponse to the lymphohematpoietic system, via a novel strategy involving IFN-gamma. A mechanistic understanding of this phenomenon will lead to the development of novel strategies for separating GVHD and GVL clinically. Core A will provide multicolor (up to 11-color) flow cytometry and high speed cell sorting services to support all of these projects. Core B (Administrative) will be responsible for administering the grant, and Core C will provide statistical and database support for all of the Projects.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA111519-02
Application #
7286055
Study Section
Subcommittee G - Education (NCI)
Program Officer
Merritt, William D
Project Start
2006-09-12
Project End
2011-07-31
Budget Start
2007-08-30
Budget End
2008-07-31
Support Year
2
Fiscal Year
2007
Total Cost
$1,884,598
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Sykes, Megan (2018) Immune monitoring of transplant patients in transient mixed chimerism tolerance trials. Hum Immunol 79:334-342
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Li, Hao Wei; Andreola, Giovanna; Carlson, Alicia L et al. (2015) Rapid Functional Decline of Activated and Memory Graft-versus-Host-Reactive T Cells Encountering Host Antigens in the Absence of Inflammation. J Immunol 195:1282-92
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Sykes, M (2015) Immune tolerance in recipients of combined haploidentical bone marrow and kidney transplantation. Bone Marrow Transplant 50 Suppl 2:S82-6
Duran-Struuck, Raimon; Huang, Christene A; Orf, Katherine et al. (2015) Miniature Swine as a Clinically Relevant Model of Graft-Versus-Host Disease. Comp Med 65:429-43
Buchan, Sarah; Manzo, Teresa; Flutter, Barry et al. (2015) OX40- and CD27-mediated costimulation synergizes with anti-PD-L1 blockade by forcing exhausted CD8+ T cells to exit quiescence. J Immunol 194:125-133
Wang, Hui; Yang, Yong-Guang (2014) The complex and central role of interferon-? in graft-versus-host disease and graft-versus-tumor activity. Immunol Rev 258:30-44
Leonard, D A; Kurtz, J M; Mallard, C et al. (2014) Vascularized composite allograft tolerance across MHC barriers in a large animal model. Am J Transplant 14:343-55
Wang, Yi; Wang, Hui; Xia, Jinxing et al. (2013) Activated CD8 T cells acquire NK1.1 expression and preferentially locate in the liver in mice after allogeneic hematopoietic cell transplantation. Immunol Lett 150:75-8

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