Graft-versus-host disease (GVHD) represents a major hurdle impeding the efficacy of allogeneic bone marrow transplantation (BMT). Bortezomib is a proteasome inhibitor that was recently approved for treatment of myeloma. We found that bortezomib potently inhibited in vitro mixed lymphocyte responses and promoted the apoptosis of alloreactive T cells. Bortezomib given at the time of allogeneic BMT in mice resulted in significant protection from acute GVHD. Reductions in GVHD-associated parameters and biological evidence of proteasome inhibition were observed with this regimen but with no adverse effects on long-term donor reconstitution. Assessment of graft-versus-tumor responses in advanced leukemia-bearing mice demonstrated that only the combination of allogeneic BMT and T cells with bortezomib promoted significant increases in survival. Increased cytotoxic T cell killing of the tumor was also observed. Thus, the combination of proteasome inhibition with selective immune attack can markedly increase the efficacy of BMT in cancer
We previously reported that interleukin-10 (IL-10) and transforming growth factor (TGF)- treatment of primary mixed lymphocyte reaction (MLR) cultures resulted in secondary alloantigen-specific hyporesponsiveness and protection from graft-versus-host disease (GVHD) lethality. Here, we report that CD4
IntroductionThe wider application of bone marrow transplantation (BMT) has been limited, in part, by graft-versus-host disease (GVHD) complications. Human and mouse mesenchymal stem cells (MSCs) have been shown to suppress allogeneic-induced and nonspecific mitogen-induced T-cell proliferation in vitro (reviewed in detail 1,2 ). Implicated suppressive mechanisms have included interleukin (IL)-10, 3 transforming growth factor (TGF)-, hepatocyte growth factor, 4 indoleamine 2,3 dioxygenase (IDO), 5 nitric oxide, 6 prostaglandin (PG) E 2 , 7 increased T-regulatory cells (Tregs), 8 and activation of the PD-1-negative costimulatory pathway. 9 In vivo, there have been conflicting data regarding the potential of MSCs to suppress GVHD. [10][11][12] Multipotent adult progenitor cells (MAPCs) are nonhematopoietic stem cells that can be copurified with MSCs from BM cells. MAPCs express the pluripotent state-specific transcription factors Oct-3/4 and Rex-1, and can differentiate into cell types representative of all 3 germ layers 13,14 ; thus, MAPCs are generally believed to be a more primitive cell type than MSCs. MSCs kept for prolonged periods in culture tend to lose their differentiation capabilities and undergo senescence at approximately 20 to 40 population doublings. 15,16 In contrast to MSCs, MAPCs have an average telomere length that remained constant for up to 100 population doublings in vitro. 13 Based upon their differential potential and reduced senescence, MAPCs have been considered as a potentially desirable nonhematopoietic stem cell source for use in allogeneic BMT. In fact, a multicenter phase 1 open label clinical trial of MultiStem, based upon MAPC technology, was initiated in 2008.In this study, we sought to determine whether MAPCs might be useful for GVHD prevention. We demonstrate that murine MAPCs are potently immune suppressive in vitro and can reduce GVHD lethality in vivo when present in the spleen, a site of initial allopriming, early post-BMT. Furthermore, we identify the mechanism of action MAPCs use to elicit T-cell inhibition and reduce GVHD-induced tissue injury in vivo. Methods MiceBALB/c (H2 d ), C57BL/6 (H2 b ; termed B6), and B10.BR (H2 k ) mice were purchased from The Jackson Laboratory or the National Institutes of Health (NIH). All mice were housed in a specific pathogen-free facility in microisolator cages and used at 8 to 12 weeks of age in protocols approved by the Institutional Animal Care and Use Committee of the University of Minnesota. MAPC isolation and cultureMAPCs were isolated from B6 and BALB/c BM, as described. 13 Briefly, BM was plated in Dulbecco modified Eagle medium/MCDB containing 10 ng/mL epidermal growth factor (Sigma-Aldrich), platelet-derived growth factor-BB (R&D Systems), leukemia inhibitory factor (Chemicon International), 2% fetal calf serum (HyClone), 1ϫ selenium-insulin-transferrinethanolamine, 0.2 mg/mL linoleic acid-bovine serum albumin (BSA), 0.8 mg/mL BSA, 1ϫ chemically defined lipid concentrate, and 1ϫ ␣-mercaptoethanol (all from Sigma-Aldrich). Cells...
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