Bone marrow transplantation (BMT) represents the best chance for cure for a large number of malignant and non-malignant hematologic diseases. However, BMT implementation is currently limited by the many critical complications that accompany this potentially life-saving therapy. This is especially true for the majority of patients (70-80%) who lack MHC-matched sibling donors, and thus face risky, unrelated and/or MHC-mismatched 'alternative-donor'transplants (AD-BMT). Three major complications have plagued the implementation of AD-BMT. They are: (1) The increased risk of graft rejection. (2) The high rate of acute graft-versus-host-disease (aGvHD) that occurs in the setting of MHC-mismatched BMT;and (3) the profound immunosuppression that patients face after transplant, which renders them highly susceptible to infectious and malignant death in the immediate and long-term post-transplant periods. Prevention and treatment of these three complications represents the major unmet clinical need in BMT. One of the most significant barriers to progress in addressing these complications has been the lack of a preclinical model through which novel biologic therapeutic strategies, developed for human use, can be thoroughly and mechanistically investigated prior to clinical trials. Thus, due to the fact that (1) most novel therapies for BMT (including T cell costimulation blockade, T cell adhesion blockade and adoptive immunotherapy with regulatory T cells) cannot be accurately tested in either murine or canine models for aGvHD and (2) there has been no other translational BMT model available to test these biologics prior to clinical use, they have remained under-analyzed and under-utilized in clinical BMT, despite their burgeoning use in other disease states. In order to address the unmet need for their detailed, translational and mechanistic investigation we have developed a novel primate model of AD-BMT, capable both of dissecting mechanism as well as providing the critical translational bridge to clinical application of novel therapies. In this proposal, we describe experiments using the primate model which will determine both mechanism and efficacy of T cell costimulation blockade, T cell adhesion blockade, and regulatory T cell adoptive immunotherapy on the outcome of AD-BMT.
Bone marrow transplantation (BMT) is the treatment of choice for many of the thousands of pediatric and adult patients each year who are diagnosed with both malignant and non-malignant hematologic diseases, including leukemia, aplastic anemia, sickle cell disease, as well as the genetic immunodeficiencies and other inborn errors of metabolism. While BMT represents the best hope for cure for these devastating disorders, it is a treatment that is fraught with complications, which continue to severely limit its wide-spread application, especially for the large majority of patients (70-80%) which lack an MHC-matched sibling bone marrow donor and thus must be transplanted using an 'alternative-donor BMT'(AD-BMT): while some of these patients without a matched sibling donor will find a highly matched unrelated donor from the registry, the wait-time to activate these donors is often prohibitive (for patients with the most aggressive malignant diseases), and many minority populations still lack adequate donors in the registry, making them far less likely to find a matched unrelated donor than patients from the ethnic majority. This research proposal thus has direct relevance to world-wide public health, in that it seeks to understand the mechanisms and efficacy of new biologic therapies for AD-BMT, in order to develop safer, and more efficacious therapeutic regimens for the thousands of patients requiring this treatment each year.
|Kaliyaperumal, Saravanan; Watkins, Benjamin; Sharma, Prachi et al. (2014) CD8-predominant T-cell CNS infiltration accompanies GVHD in primates and is improved with immunoprophylaxis. Blood 123:1967-9|
|Singh, K; Stempora, L; Harvey, R D et al. (2014) Superiority of rapamycin over tacrolimus in preserving nonhuman primate Treg half-life and phenotype after adoptive transfer. Am J Transplant 14:2691-703|
|Huang, Alex Y; Haining, W Nicholas; Barkauskas, Deborah S et al. (2013) Viewing transplantation immunology through today's lens: new models, new imaging, and new insights. Biol Blood Marrow Transplant 19:S44-51|
|Johnson, Z P; Eady, R D; Ahmad, S F et al. (2012) Immunogenetic Management Software: a new tool for visualization and analysis of complex immunogenetic datasets. Immunogenetics 64:329-36|
|Page, A; Srinivasan, S; Singh, K et al. (2012) CD40 blockade combines with CTLA4Ig and sirolimus to produce mixed chimerism in an MHC-defined rhesus macaque transplant model. Am J Transplant 12:115-25|
|Kean, L S; Singh, K; Blazar, B R et al. (2012) Nonhuman primate transplant models finally evolve: detailed immunogenetic analysis creates new models and strengthens the old. Am J Transplant 12:812-9|
|Kean, Leslie S; Sen, Sharon; Onabajo, Olusegun et al. (2011) Significant mobilization of both conventional and regulatory T cells with AMD3100. Blood 118:6580-90|
|Miller, Weston P; Srinivasan, Swetha; Panoskaltsis-Mortari, Angela et al. (2010) GVHD after haploidentical transplantation: a novel, MHC-defined rhesus macaque model identifies CD28- CD8+ T cells as a reservoir of breakthrough T-cell proliferation during costimulation blockade and sirolimus-based immunosuppression. Blood 116:5403-18|