This project addresses two major barriers to progress in allogeneic hematopoietic stem cell transplantation (HSCT): graft-vs-host disease (GvHD) and relapse. A novel strategy is proposed that challenges the prevailing practice of trying to curtail donor T cell alloreactivity after the fact, to one of controlling the afferent sensitization of lymphocyte effectors at the level of antigen-presentation by dendritic cells (DCs). DCs comprise a heterogeneous population of potent antigen-presenting cells, which initiate immunity and control its quality. We hypothesize that the undesirable complications of GvHD can be separated from the beneficial GvL effects exerted by allogeneic HSCT, based on differences in afferent sensitization of immune responses by distinct DC subtypes. This hypothesis will be addressed in the following specific aims:
SPECIFIC AIM 1 : Determine whether allogeneic interactions between human Langerhans-type DCs (LCs) and T cells in vitro are abrogated by inhibition of JAK2-STAT3 signaling, and whether the capacity of WTI mRNA- electroporated LCs remains intact to break tolerance against this self-differentiation tumor Ag by an IL15- dependent mechanism.
SPECIFIC AIM 2 : Compare and contrast the inhibition of JAK2-STAT3 in NK cells stimulated by monocyte-derived DCs (moDCs) via an IL12p70-dependent mechanism, with JAK2 inhibition of moDC-stimulated allogeneic T cells.
SPECIFIC AIM 3 : Evaluate the mechanism of JAK2 inhibition with respect to alloreactivity and tumor immunity in defined mouse transplant models. Successful inhibition of the JAK2-pSTAT3 pathway, which would block at least moDC-derived IL6 and IL23 cytokine effects on alloreactive lymphocytes, would lead to the use of an entirely new class of drugs for prevention and treatment of GvHD. This would maintain freedom from relapse (GvL) and infectious morbidity and mortality brought on by less selective immune suppression. The approach would also take full advantage of the potency of W T I mRNA-electroporated LCs to break tolerance and stimulate effective CTLs against this broadly-expressed, self-differentiation tumor Ag. Successful completion ofthese aims will fundamentally alter management of graft-host interactions in the context of allogeneic HSCT by controlling immune responses regulated by distinct DC subsets from their onset. These studies will also have broader public health potential to improve management of immune suppression and prevention of graft rejection in solid organ transplantation.
Dendritic cells (DCs) are master orchestrators ofthe immune response. The two main barriers to successful blood and marrow stem cell transplantation are graft-vs-host disease (GvHD) and relapse. These will be addressed by a new class of drug that interferes with signaling from specific DC subtypes to responding lymphocytes, to curb immune reactions against transplant recipients (GvHD) but maintain freedom from relapse. Results will also have implications for management of solid organ transplants to prevent rejection.
|Tarek, N; Gallagher, M M; Chou, J F et al. (2015) KIR and HLA genotypes have no identifiable role in single-unit dominance following double-unit umbilical cord blood transplantation. Bone Marrow Transplant 50:150-2|
|Hubbard-Lucey, Vanessa M; Shono, Yusuke; Maurer, Katie et al. (2014) Autophagy gene Atg16L1 prevents lethal T cell alloreactivity mediated by dendritic cells. Immunity 41:579-91|
|Dubrovsky, Leonid; Pankov, Dmitry; Brea, Elliott Joseph et al. (2014) A TCR-mimic antibody to WT1 bypasses tyrosine kinase inhibitor resistance in human BCR-ABL+ leukemias. Blood 123:3296-304|
|Maguire, William F; McDevitt, Michael R; Smith-Jones, Peter M et al. (2014) Efficient 1-step radiolabeling of monoclonal antibodies to high specific activity with 225Ac for ?-particle radioimmunotherapy of cancer. J Nucl Med 55:1492-8|
|Olson, Amanda L; Dahi, Parastoo B; Zheng, Junting et al. (2014) Frequent human herpesvirus-6 viremia but low incidence of encephalitis in double-unit cord blood recipients transplanted without antithymocyte globulin. Biol Blood Marrow Transplant 20:787-93|
|Curran, Shane A; Romano, Emanuela; Kennedy, Michael G et al. (2014) Phenotypic and functional activation of hyporesponsive KIRnegNKG2Aneg human NK-cell precursors requires IL12p70 provided by Poly(I:C)-matured monocyte-derived dendritic cells. Cancer Immunol Res 2:1000-10|
|Dahi, P B; Ponce, D M; Devlin, S et al. (2014) Donor-recipient allele-level HLA matching of unrelated cord blood units reveals high degrees of mismatch and alters graft selection. Bone Marrow Transplant 49:1184-6|
|Dahi, Parastoo B; Ponce, Doris M; Devlin, Sean et al. (2014) "No wash" albumin-dextran dilution for double-unit cord blood transplantation is safe with high rates of sustained donor engraftment. Biol Blood Marrow Transplant 20:490-4|
|Tyler, Eleanor M; Jungbluth, Achim A; Gnjatic, Sacha et al. (2014) Cancer-testis antigen 7 expression and immune responses following allogeneic stem cell transplantation for multiple myeloma. Cancer Immunol Res 2:547-58|
|Pai, Sung-Yun; Logan, Brent R; Griffith, Linda M et al. (2014) Transplantation outcomes for severe combined immunodeficiency, 2000-2009. N Engl J Med 371:434-46|
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