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The Role of Apoptosis in the Ameliorating Effects of a CDR1-Based Peptide on Lupus Manifestations in a Mouse Model¹

Department of Immunology, Weizmann Institute of Science, Rehovot, Israel

Experimental systemic lupus erythematosus (SLE) can be induced in mice following immunization with an anti-DNA mAb expressing a major Id, 16/6Id. Treatment with a peptide, designated human CDR1 (hCDR1; Edratide), that is based on the sequence of CDR1 of the 16/6Id ameliorated disease manifestations. In the present study, we investigated the roles of apoptosis and related molecules in BALB/c mice with induced experimental SLE following treatment with hCDR1. A higher state of activation and increased rate of apoptosis were found in lymphocytes of SLE-afflicted mice as compared with healthy controls. The latter effects were associated with up-regulated caspase-8 and caspase-3, and down-regulated Bcl-x_L. The ameliorative effects of hCDR1 were associated with down-regulation of caspase-8 and caspase-3, up-regulation of Bcl-x_L, and a reduced rate of apoptosis. Treatment of diseased mice with an apoptosis-reducing compound that inhibited caspases down-regulated the secretion of the pathogenic cytokine IFN- and lowered the intensity of glomerular immune complex deposits and the levels of proteinuria. Furthermore, coincubation of Bcl-x_L inhibitors with hCDR1-treated cells abrogated the ability of hCDR1 to reduce the activation state of lymphocytes and to down-regulate the secretion of IL-10 and IFN-. Moreover, the Bcl-x_L-expressing CD4⁺CD25⁺ cells from hCDR1-treated mice induced the expression of Bcl-x_L in CFSE-labeled CD4⁺CD25^– cells of the SLE-afflicted mice. Thus, the reduction of apoptosis and the up-regulation of Bcl-x_L, which plays an apparent role in tolerance induction, contribute to at least part of the beneficial effects of hCDR1 on lupus manifestations.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Teva Pharmaceutical Industries, Israel.

² Address correspondence and reprint requests to Dr. Edna Mozes, Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel. E-mail address: edna.mozes{at}weizmann.ac.il

³ Abbreviations used in this paper: SLE, systemic lupus erythematosus; BWF₁, (New Zealand Black x New Zealand White)F₁; FasL, Fas ligand; hCDR1, human CDR1; ICD, immune complex deposit; LN, lymph node; PI, propidium iodide; ZVAD-fmk, carbobenzoxy-valyl-alanyl-aspartyl-(-o-methyl) fluoromethylketone.

This article has been cited by other articles:

				A. Sharabi and E. Mozes The Suppression of Murine Lupus by a Tolerogenic Peptide Involves Foxp3-Expressing CD8 Cells That Are Required for the Optimal Induction and Function of Foxp3-Expressing CD4 Cells J. Immunol., September 1, 2008; 181(5): 3243 - 3251. [Abstract] [Full Text] [PDF]