Bcl-2 as a Therapeutic Target in Human Tubulointerstitial Inflammation

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Abstract

<div class="section"> <a class="named-anchor" id="S1">  </a> <h5 class="section-title" id="d1584510e274">Objective</h5> <p id="P2">In lupus nephritis (LuN), tubulointerstitial inflammation (TII) is associated with <i>in situ</i> adaptive immune cell networks that amplify local tissue damage. As patients with severe TII often fail conventional therapy and develop renal failure, understanding these <i>in situ</i> mechanisms might reveal new therapeutic targets. We hypothesized that in TII, dysregulated apoptotic regulators maintain local adaptive immunity and drive inflammation. </p> </div><div class="section"> <a class="named-anchor" id="S2">  </a> <h5 class="section-title" id="d1584510e285">Methods</h5> <p id="P3">We developed novel computational approaches that, when applied to multicolor confocal images, quantified apoptotic regulator protein expression in selected lymphocyte subsets. This approach was validated using laser capture microdissection (LCM) coupled to qPCR. Furthermore, we explored the consequences of dysregulated apoptotic mediator expression in a murine model of LuN. </p> </div><div class="section"> <a class="named-anchor" id="S3">  </a> <h5 class="section-title" id="d1584510e290">Results</h5> <p id="P4">Analyses of renal biopsies from LuN and mixed cellular allograft rejection patients revealed that BCL-2 was frequently expressed in infiltrating lymphocytes while expression of MCL-1 was low. In contrast, the reciprocal pattern of expression was observed in tonsil germinal centers. These results were consistent with RNA expression data obtained using LCM and qPCR. BCL-2 was also highly expressed in tubulointerstitial infiltrates of <i>NZB/W</i> F <sub>1</sub> mice. Furthermore, treatment of <i>NZB/W</i> F <sub>1</sub> mice with ABT-199, a selective oral inhibitor of BCL-2, prolonged survival and prevented proteinuria and development of TII in a prevention model. Interestingly, glomerular immune complexes were partially ameliorated by ABT-199 and serum anti-dsDNA antibody titers were unaffected. </p> </div><div class="section"> <a class="named-anchor" id="S4">  </a> <h5 class="section-title" id="d1584510e307">Conclusion</h5> <p id="P5">These data demonstrate BCL-2 as an attractive therapeutic target in LuN manifesting TII. </p> </div>

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Development and maintenance of B and T lymphocytes requires antiapoptotic MCL-1.

Joseph T. Opferman, Anthony Letai, Caroline Beard … (2003)

Regulated apoptosis is essential for both the development and the subsequent maintenance of the immune system. Interleukins, including IL-2, IL-4, IL-7 and IL-15, heavily influence lymphocyte survival during the vulnerable stages of VDJ rearrangement and later in ensuring cellular homeostasis, but the genes specifically responsible for the development and maintenance of lymphocytes have not been identified. The antiapoptotic protein MCL-1 is an attractive candidate, as it is highly regulated, appears to enhance short-term survival and functions at an apical step in genotoxic deaths. However, Mcl-1 deficiency results in peri-implantation lethality. Here we show that mice conditional for Mcl-1 display a profound reduction in B and T lymphocytes when MCL-1 is removed. Deletion of Mcl-1 during early lymphocyte differentiation increased apoptosis and arrested the development at pro-B-cell and double-negative T-cell stages. Induced deletion of Mcl-1 in peripheral B- and T-cell populations resulted in their rapid loss. Moreover, IL-7 both induced and required MCL-1 to mediate lymphocyte survival. Thus, MCL-1, which selectively inhibits the proapoptotic protein BIM, is essential both early in lymphoid development and later on in the maintenance of mature lymphocytes.

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Defective B cell tolerance checkpoints in systemic lupus erythematosus

Sergey Yurasov, Hedda Wardemann, Johanna E Hammersen … (2005)

A cardinal feature of systemic lupus erythematosus (SLE) is the development of autoantibodies. The first autoantibodies described in patients with SLE were those specific for nuclei and DNA, but subsequent work has shown that individuals with this disease produce a panoply of different autoantibodies. Thus, one of the constant features of SLE is a profound breakdown in tolerance in the antibody system. The appearance of self-reactive antibodies in SLE precedes clinical disease, but where in the B cell pathway tolerance is first broken has not been defined. In healthy humans, autoantibodies are removed from the B cell repertoire in two discrete early checkpoints in B cell development. We found these checkpoints to be defective in three adolescent patients with SLE. 25–50% of the mature naive B cells in SLE patients produce self-reactive antibodies even before they participate in immune responses as compared with 5–20% in controls. We conclude that SLE is associated with abnormal early B cell tolerance.