SDF-1alpha as an immunosuppressant
Kofi
CXCL12 (SDF-1alpha) suppresses ongoing experimental autoimmune
encephalomyelitis by selecting antigen-specific regulatory T cells.
Meiron M, Zohar Y, Anunu R, Wildbaum G, Karin N.
Department of Immunology, Bruce Rappaport Faculty of Medicine, Technion,
Haifa 31096, Israel.
Experimental autoimmune encephalomyelitis (EAE) is a T cell-mediated
autoimmune disease of the central nervous system induced by
antigen-specific effector Th17 and Th1 cells. We show that a key
chemokine, CXCL12 (stromal cell-derived factor 1alpha), redirects the
polarization of effector Th1 cells into CD4(+)CD25(-)Foxp3(-)interleukin
(IL) 10(high) antigen-specific regulatory T cells in a CXCR4-dependent
manner, and by doing so acts as a regulatory mediator restraining the
autoimmune inflammatory process. In an attempt to explore the
therapeutic implication of these findings, we have generated a
CXCL12-immunoglobulin (Ig) fusion protein that, when administered during
ongoing EAE, rapidly suppresses the disease in wild-type but not
IL-10-deficient mice. Anti-IL-10 neutralizing antibodies could reverse
this suppression. The beneficial effect included selection of
antigen-specific T cells that were CD4(+)CD25(-)Foxp3(-)IL-10(high),
which could adoptively transfer disease resistance, and suppression of
Th17 selection. However, in vitro functional analysis of these cells
suggested that, even though CXCL12-Ig-induced tolerance is IL-10
dependent, IL-10-independent mechanisms may also contribute to their
regulatory function. Collectively, our results not only demonstrate, for
the first time, that a chemokine functions as a regulatory mediator, but
also suggest a novel way for treating multiple sclerosis and possibly
other inflammatory autoimmune diseases.
Publication Types:
* Comparative Study
* Research Support, Non-U.S. Gov't
PMID: 18852294