Conventional therapies for antibody removal consisting of plasma exchange with IVIG and Rituximab are partially effective in desensitization protocols and for treatment of antibody mediated rejection (AMR) in thoracic transplant recipients. Newer therapies with proteasome inhibitors like Carfilzomib (CFZ) that target B and plasma cells may be more effective.We evaluated the impact of desensitization therapy in 3 heart candidates (HTx) (2 CFZ , 1 conventional) and in 4 lung transplant recipients (LTx) treated with CFZ for persistent AMR. We measured HLA antibody levels, complement binding and composition and level of IgG subtypes (IgG1-4). All 7 patients had HLA antibody specificity, and IgG subtypes measured by single antigen bead assay (SAB) and complement binding by C1q screen at base-line and post-treatment at 1 and 3 months. We correlated the response to therapy with changes in antibody function and IgG subtype. All 3 sensitized candidates that had a cPRA by C1q screen >85% have been successfully transplanted (2 HTx, 1LTx) following therapy. Among 4 LTx treated for AMR, 2 responded and 2 failed. In all 7 patients we observed a mixture of IgG subtypes consisting of complement fixing (CF) IgG1/3 and non-complement fixing (NCF) IgG2/4. The response to therapy was associated with loss of C1q reactivity. Although the IgG subtype composition remained the same, IgG1-4 levels declined in responders. HTx candidate with 95% C1q cPRA had 18 HLA Class I antibodies that were IgG1 (5,000-10,000 MFI) and IgG2 (15,000-25,000 MFI) at baseline; the cPRA by C1q became 0% with the same IgG1/2 profile but at lower levels <3000 MFI. In contrast, pan-IgG MFI for all the HLA antibodies did not change (8,000-15,000 MFI). The IgG subtype and C1q reactivity of a responder (R) and a failed (F) LTx treated for AMR is shown below. Response to therapy correlated with loss of C1q DSA and drop in IgG subtype levels whereas the non-responder remained the same.

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