ps1145 and Graft-vs-Host-Disease

The ex vivo induction of alloantigen-specific hyporesponsiveness by costimulatory pathway blockade or exposure to immunoregulatory cytokines has been shown to inhibit proliferation, IL-2 production, and the graft-versus-host disease (GVHD) capacity of adoptively transferred T-cells. We hypothesized that inhibition of the intracellular NF-kappaB pathway in alloreactive T-cells, which is critical for T-cell activation events including IL-2 transcription, could lead to alloantigen hyporesponsiveness and loss of GVHD capacity. We demonstrate that treatment of mixed lymphocyte reaction (MLR) cultures with PS1145, a potent inhibitor of NF-kappaB activation, can induce T-cell hyporesponsiveness to alloantigen in primary and secondary responses while preserving in vitro responses to potent mitogenic stimulation. GVHD lethality in recipients of ex vivo PS1145-treated cells was profoundly inhibited. Parking of control or PS1145-treated MLR cells in syngeneic Rag(-/-) recipients resulted in intact contact hypersensitivity (CHS) responses. However, GVHD lethality capacity also was restored, suggesting that lymphopenic expansion uncoupled alloantigen hyporesponsiveness. These results indicate that the NF-kappaB pathway is a critical regulator of alloresponses and provide a novel small molecule inhibitor based approach that is effective in preventing early posttransplant GVHD lethality but that also permits donor T-cell responses to recover after a period of lymphopenic expansion.

Topics: Animals; Apoptosis; Cell Proliferation; Cells, Cultured; Female; Graft vs Host Disease; Heterocyclic Compounds, 3-Ring; Isoantigens; Lymphocyte Culture Test, Mixed; Male; Mice; Models, Immunological; NF-kappa B; Pyridines; Signal Transduction; T-Lymphocytes

NF-kappaB is a transcription factor that controls the expression of a number of genes important for mediating immune and inflammatory responses. In this study, we examined whether bortezomib and PS-1145, each of which inhibits NF-kappaB, could protect mice from lethal graft-versus-host disease (GVHD), which is characterized by immune activation and proinflammatory cytokine production. When administered within the first 2 days after transplantation, bortezomib and PS-1145 both protected mice from fatal GVHD, did not compromise donor engraftment, and effected marked reduction in the levels of serum cytokines that are normally increased during GVHD. Extending the course of bortezomib administration or delaying the initiation of this agent for as few as 3 days after bone marrow transplantation (BMT), however, significantly exacerbated GVHD-dependent mortality because of severe pathological damage in the colon. In contrast, prolonged administration of PS-1145, which, unlike bortezomib, is a selective inhibitor of NF-kappaB, caused no early toxicity and resulted in more complete protection than that observed with an abbreviated PS-1145 treatment schedule. These results confirm a critical role for NF-kappaB in the pathophysiology of GVHD and indicate that targeted inhibition of NF-kappaB may have a superior therapeutic index and may constitute a viable therapeutic approach to reduce GVHD severity.

Topics: Animals; Antineoplastic Agents; Bone Marrow Transplantation; Boronic Acids; Bortezomib; Colon; Cytokines; Graft Survival; Graft vs Host Disease; H-2 Antigens; Heterocyclic Compounds, 3-Ring; Leukocyte Common Antigens; Mice; Mice, Knockout; NF-kappa B; Pyrazines; Pyridines; Survival Rate