Reversal of cancer cachexia and muscle wasting by ActRIIB antagonism leads to prolonged survival.

Muscle wasting and cachexia have long been postulated to be key determinants of cancer-related death, but there has been no direct experimental evidence to substantiate this hypothesis. Here, we show that in several cancer cachexia models, pharmacological blockade of ActRIIB pathway not only prevents further muscle wasting but also completely reverses prior loss of skeletal muscle and cancer-induced cardiac atrophy. This treatment dramatically prolongs survival, even of animals in which tumor growth is not inhibited and fat loss and production of proinflammatory cytokines are not reduced. ActRIIB pathway blockade abolished the activation of the ubiquitin-proteasome system and the induction of atrophy-specific ubiquitin ligases in muscles and also markedly stimulated muscle stem cell growth. These findings establish a crucial link between activation of the ActRIIB pathway and the development of cancer cachexia. Thus ActRIIB antagonism is a promising new approach for treating cancer cachexia, whose inhibition per se prolongs survival.

Posttransplant administration of allochimeric major histocompatibility complex class-I-molecules induces true transplantation tolerance.

BACKGROUND: Allochimeric class-I major histocompatibility complex (MHC) molecules that contain donor-type immunogenic epitopes displayed on recipient-type sequences were shown to induce transplantation tolerance when administered at the time of transplantation. Here, we investigated the ability of posttransplant allochimeric administration to induce tolerance and concomitantly inhibit chronic rejection. METHODS: Allochimeric (alpha1h(1/u))-RT1.Aa class-I MHC antigenic extracts were administered by way of the portal vein into ACI recipients of Wistar-Firth (WF) hearts at days +3, +7, and +10 posttransplantation in conjunction with subtherapeutic oral cyclosporine. RESULTS: Delayed posttransplant allochimeric administration induced donor-specific transplantation tolerance to rat cardiac allografts. In contrast, delayed delivery of unaltered donor- or recipient-type MHC extracts failed to prolong allograft survival. In addition, histopathologic examination or estimation of transplant vascular sclerosis by neointimal index assessment, following delayed allochimeric therapy, revealed intact global architecture and minimal intimal thickening, respectively. CONCLUSION: Allochimeric MHC class-I therapy is a unique and novel clinically applicable approach for induction of "true" transplantation tolerance where chronic rejection is concomitantly abrogated.

A novel mechanism for the immunomodulatory functions of class II MHC-derived peptides.

There is now extensive evidence that synthetic peptides corresponding to linear sequences of MHC molecules are effective immunoregulators, targeting the immune response at many different sites. It has been previously shown that peptides derived from a highly conserved region of MHC class II inhibit proliferation to autoantigen and to both the direct and indirect pathways of allorecognition. This study demonstrates that inhibition of lymphocyte proliferation by nonpolymorphic MHC class II peptides, specifically HLA-DQA1, is sequence-specific and that the inhibitory effect is mediated through the induction of apoptosis in antigen-presenting cells via a caspase-independent mechanism. In addition, T lymphocytes stimulated in the presence of HLA-DQA1 are rendered hyporesponsive to subsequent stimuli. Immunomodulation by HLA-DQA1 is effective in vivo because it prevents both the priming and the effector function of primed allogeneic T cells in a murine DTH model. These observations have important implications for the development of a novel therapy for immune-mediated diseases.