A comparative analysis between proteasome and immunoproteasome inhibition in cellular and humoral alloimmunity

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Abstract

Triggered by the successful administration of the proteasome inhibitor bortezomib in kidney transplant recipients with acute or chronic antibody-mediated rejection, we evaluated the effect of the proteasome inhibitor CEP-18770 and of the selective immunoproteasome inhibitor ONX-0914 on cellular and humoral alloimmunity. Cellular alloimmunity was assessed by cell proliferation in a two-way mixed lymphocyte reaction (MLR) with human peripheral blood mononuclear cells (PBMC). For assessing humoral alloimmunity we developed a method, where humoral alloimmunity was induced in one-way MLR. The de novo production of alloantibodies was measured with an antibody-mediated complement-dependent cytotoxicity assay, in which supernatants from the above MLRs were used against resting PBMC similar to the stimulator cells of the forementioned MLRs. In two-way MLRs ONX-0914 inhibited cell proliferation more than CEP-18770. In one-way MLRs CEP-18770 and ONX-0194 decreased alloantibody production to the same extent. Inhibition of the immunoproteasome is superior to inhibition of the proteasome in suppressing cellular alloimmunity, and equally effective as regards to humoral alloimmunity. Considering the selective expression of the immunoproteasome in immune cells and the expected restrictive toxicity of its inhibitors, these results render immunoproteasome an excellent target for the development of new immunosuppressive medications in the field of transplantation.

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