A tolerogenic peptide down‐regulates mature B cells in bone marrow of lupus‐afflicted mice by inhibition of interleukin‐7, leading to apoptosis

Abstract

Summary Systemic lupus erythematosus (SLE) is an autoimmune disease mediated by T and B cells. It is characterized by a variety of autoantibodies and systemic clinical manifestations. A tolerogenic peptide, designated hCDR1, ameliorated the serological and clinical manifestations of SLE in both spontaneous and induced models of lupus. In the present study, we evaluated the status of mature B cells in the bone marrow (BM) of SLE‐afflicted mice, and determined the effect of treatment with the tolerogenic peptide hCDR1 on these cells. We demonstrate herein that mature B cells of the BM of SLE‐afflicted (New Zealand Black × New Zealand White)F1 mice were largely expanded, and that treatment with hCDR1 down‐regulated this population. Moreover, treatment with hCDR1 inhibited the expression of the pathogenic cytokines [interferon‐γ and interleukin (IL)‐10], whereas it up‐regulated the expression of transforming growth factor‐β in the BM. Treatment with hCDR1 up‐regulated the rates of apoptosis of mature B cells. The latter was associated with inhibited expression of the survival Bcl‐xL gene and of IL‐7 by BM cells. Furthermore, the addition of recombinant IL‐7 abrogated the suppressive effects of hCDR1 on Bcl‐xL in the BM cells and resulted in elevated levels of apoptosis. Hence, the down‐regulated production of IL‐7 contributes to the hCDR1‐mediated apoptosis of mature B cells in the BM of SLE‐afflicted mice.

The Tolerogenic Peptide, hCDR1, Down-Regulates the Expression of Interferon-α in Murine and Human Systemic Lupus Erythematosus

“…Those beneficial effects resulted from the effects of hCDR1 on different immune cell types (including dendritic [22], T [9], [17], [34] and B cells [20], [21], [35]) and on cytokines [9], [11]. Thus, hCDR1 down regulated (in vivo and in vitro, in murine SLE models and in human lupus) pro-inflammatory cytokines [11], [23], [24], apoptotic factors [18], [19], [23], [24], [36], B-cell stimulatory factors (BAFF/BLyS) [20], [24] and up regulated immunosuppressive cytokines [9], [11], [23], [24], [37] with the induction of CD4+CD25+FoxP3+regulatory T-cells [15], [23].…”

Effects of Peptide-Induced Immune Tolerance on Murine Lupus

“…The reduced levels of BAFF correlated with reduced rate of maturation and differentiation of B cells and decrease in integrin expression. Recent studies provided further evidence of targeting of BAFF/BLys and APRIL in the management of lupus ( 86 – 88 ); and another study reported the effect of hCDR1 on IL-7 and apoptosis ( 89 ) and showed the rate of apoptosis is reduced with hCDR1 treatment in lupus mice. Bcl2 and Bcl- XL levels were further reduced, and this was associated with reduced activation of T and B cells ( 90 ).…”