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Background: Long-lived plasma cells (PCs) that form after alloantigen sensitization produce donor-specific alloantibodies that generate a positive serum crossmatch and preclude transplantation. New approaches for desensitization, including PC depletion with proteasome inhibition, show promise but carry considerable toxicity. Recently, eosinophils have been shown to govern PC persistence. Interleukin 5 (IL-5) depletion is known to reduce eosinophils in human asthmatics. We hypothesized that treatment with an anti-IL-5 antibody can deplete alloreactive PCs, reduce donor-specific alloantibodies, and serve as a less toxic alternative to proteasome inhibition., Methods: BALB/c mice were sensitized with B6 skin allografts. Starting at 8 wk after sensitization, control mice received injections of phosphate-buffered saline, whereas experimental mice received weekly injections of an anti-IL-5 antibody. PCs were enumerated by enzyme-linked immunosorbent spot after 8 wk., Results: All control and experimental recipients of skin allografts developed positive crossmatches when screened at 8 wk after sensitization. All experimental mice treated with anti-IL-5 showed a reduction in their total PC numbers. Also, in contrast to the known adverse effects of proteasome inhibition, experimental mice treated with anti-IL-5 exhibited negligible weight loss or lymphopenia., Conclusions: Treatment with anti-IL-5 is sufficient to reduce, but not eliminate, alloreactive PCs in the bone marrow. This is because of the targeted reduction of eosinophils leading to a reduction in the PC survival factors a proliferation-inducing ligand and IL-6. Generalized toxicity was not observed in experimental mice. Overall, IL-5 directed immunotherapy can eliminate PC's but is unlikely to be a clinically significant desensitization strategy given the persistence of DSA., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The current mainstay of immunotherapy in clinical transplantation is T lymphocyte directed. However, it has long been appreciated that the emergence of an alloimmune response mounted by the B lymphocyte compartment and detectable as donor-specific antibodies is a critical challenge to long-term graft survival. Thus, achieving robust transplantation tolerance will require induction of tolerance in both the T- and B-cell compartments. Here we propose that the natural developmental propensity of the B-lymphocyte compartment acquisition of tolerance to self-antigens can be recapitulated to achieve humoral transplantation tolerance. It is our contention B-lymphocyte directed induction immunotherapy would be an important component of emerging strategies for induction of Transplantation tolerance., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

T helper (Th) 1-mediated immune responses are associated with adverse outcomes in a number of models of autoimmune disease. Previous work has focused on the role that cytokines secreted by Th1 cells play in mediating pathologic tissue injury. To evaluate other mechanisms by which Th1 cells may be specialized to coordinate the complex effector cell interactions of a destructive immune response, CD4+ T cells specific for influenza hemagglutinin (HA) were differentiated into Th1 or Th2 subsets and transferred into transgenic mice expressing HA under control of the beta myosin heavy chain promoter, which drives heart specific expression of HA. CD4+ T cells polarized to a Th1 phenotype mediated a more destructive myocarditis than Th2 cells. Strikingly, the Th1-mediated inflammation was comprised primarily of CD8+ T cells and macrophages, suggesting a specialized recruitment function for Th1 cells. Further studies revealed that Th1 and Th2 subsets had polarized secretion of certain CC-chemokines, including MIP-1alpha and RANTES, which have selective recruitment properties on effector cells. Th1 cell secreted factors were up to 1000-fold more potent in inducing CD8+ T cell migration compared to Th2 cell secreted factors, and this advantage was partially mediated by their specialized MIP-1alpha secretion. These findings indicate that Th subsets have distinct patterns of CC-chemokine secretion and this specialization by Th1 cells mediates the recruitment of cytotoxic effector cells into destructive inflammatory responses.