Cell-based diabetes therapy requires an abundant cell source. Here, we report reversal of diabetes for more than 100 d in cynomolgus macaques after intraportal transplantation of cultured islets from genetically unmodified pigs without Gal-specific antibody manipulation. Immunotherapy with CD25-specific and CD154-specific monoclonal antibodies, FTY720 (or tacrolimus), everolimus and leflunomide suppressed indirect activation of T cells, elicitation of non-Gal pig-specific IgG antibody, intragraft expression of proinflammatory cytokines and invasion of infiltrating mononuclear cells into islets.
Peripheral T-cell tolerance is a mechanism to limit autoimmunity, but represents a major obstacle in diseases such as cancer. Tolerance is due to limited accumulation of antigen-specific T cells accompanied by functional hypo-responsiveness, and is induced by antigen encounter in a non-inflammatory environment. In contrast to advances in preventing induction of T-cell tolerance, there has been little progress in defining targets to reverse established tolerance. Here we show that signals from a single dose of an agonistic antibody against OX40 (CD134, a member of the tumor necrosis-factor family of receptors) can break an existing state of tolerance in the CD4+ T-cell compartment. OX40 signals promote T-cell expansion after the hypo-responsive phenotype is induced and restore normal functionality. These data highlight the potent costimulatory capacity of OX40, and indicate OX40 as a target for therapeutic intervention in a variety of related diseases.
The persistence of functional CD8 T cell responses is dependent on checkpoints established during priming. Although naive CD8 cells can proliferate with a short period of stimulation, CD4 help, inflammation, and/or high peptide affinity are necessary for the survival of CTL and for effective priming. Using OX40-deficient CD8 cells specific for a defined Ag, and agonist and antagonist OX40 reagents, we show that OX40/OX40 ligand interactions can determine the extent of expansion of CD8 T cells during responses to conventional protein Ag and can provide sufficient signals to confer CTL-mediated protection against tumor growth. OX40 signaling primarily functions to maintain CTL survival during the initial rounds of cell division after Ag encounter. Thus, OX40 is one of the costimulatory molecules that can contribute signals to regulate the accumulation of Ag-reactive CD8 cells during immune responses.
We sought to determine the long-term outcomes in type 1 diabetic recipients of intraportal alloislet transplants on a modified immunosuppressive protocol. Six recipients with hypoglycemia unawareness received 1 to 2 islet infusions. Induction therapy was with antithymocyte globulin (ATG) plus etanercept for tumor necrosis factor-α blockade. Recipients received cyclosporine and everolimus for maintenance immunosuppression for the first year posttransplant, with mycophenolic acid or mycophenolate mofetil subsequently substituted for everolimus. Recipients have been followed for 1173 ± 270 days since their last infusion for islet graft function (insulin independence, hemoglobin A1c levels, and C-peptide production) and for adverse events associated with the study protocol. Of the 6 recipients, 5 were insulin-independent at 1 year, and 4 continue to be insulin-independent at a mean of 3.4 ± 0.4 years posttransplant. None of the 6 recipients experienced recurrence of severe hypoglycemia. Measured glomerular filtration rate decreased from 110.5 ±21.2 mL/min/1.73m2 pretransplant to 82.6 ±19.1 mL/min/1.73m2 at 1 year posttransplant. In conclusion, islet transplants restored insulin independence for a mean of >3 years in 4 of 6 recipients treated with ATG and etanercept induction therapy and with cyclosporine and, initially, everolimus for maintenance. Our results suggest this immunosuppressive protocol may allow long-term graft survival.
4–1BB is expressed on activated T cells. We analyzed the role of 4–1BB during the CD8 T cell response of OT‐I TCR‐transgenic T cells to ovalbumin. In vitro, blocking 4–1BB during peptide presentation reduced proliferation of naive CD8 T cells, but did not affect the generation of CTL. Using an in vivo adoptive transfer model, clonal expansion of CD8 T cells to whole protein in adjuvant was significantly reduced when 4–1BB was blocked, with 50–70% fewer CD8 T cells accumulating. This was due to a reduction in T cell division and to enhanced apoptosis of CD8 T cellsthat had undergone many divisions. T cells generated in the absence of 4–1BB were impaired in their ability to secrete IFN‐γ whereas CTL activity of the T cells that survived was unaffected. These findings demonstrate that 4–1BB contributes to clonal expansion, survival, and development of Tc1 cells when protein antigen is encountered by primary CD8 T cells in an inflammatory environment in vivo.
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