Reduced Chemokine and Chemokine Receptor Expression in Spinal Cords of TCR BV8S2 Transgenic Mice Protected Against Experimental Autoimmune Encephalomyelitis with BV8S2 Protein

Abstract

The perivascular transmigration and accumulation of macrophages and T lymphocytes in the CNS of mice with experimental autoimmune encephalomyelitis (EAE) may be partly regulated by low m.w. chemotactic cytokines. Using the RNase protection assay and ELISA, we quantified expression of chemokines and chemokine receptors in the spinal cord (SC), brain, and lymph nodes of BV8S2 transgenic mice that developed or were protected from EAE by vaccination with BV8S2 protein. In paralyzed control mice, the SC had increased cellular infiltration and strong expression of the chemokines RANTES, IFN-inducible 10-kDa protein, and monocyte chemoattractant protein-1 and the cognate chemokine receptors CCR1, CCR2, and CCR5, with lower expression of macrophage-inflammatory protein (MIP)-1α, MIP-1β, and MIP-2; whereas brain had less infiltration and a lower expression of a different pattern of chemokines and receptors. In TCR-protected mice, there was a decrease in the number of inflammatory cells in both SC and brain. In SC, the reduced cellular infiltrate afforded by TCR vaccination was commensurate with profoundly reduced expression of chemokines and their cognate chemokine receptors. In brain, however, TCR vaccination did not produce significant changes in chemokine expression but resulted in an increased expression of CCR3 and CCR4 usually associated with Th2 cells. In contrast to CNS, lymph nodes of protected mice had a significant increase in expression of MIP-2 and MIP-1β but no change in expression of chemokine receptors. These results demonstrate that TCR vaccination results in selective reduction of inflammatory chemokines and chemokine receptors in SC, the target organ most affected during EAE.

Transfer of Severe Experimental Autoimmune Encephalomyelitis by IL-12- and IL-18-Potentiated T Cells Is Estrogen Sensitive

“…CCR5 expression is required for cells to move from secondary lymphoid tissue to the inflamed sites in the periphery. Up-regulation of CCR5 expression on T and B cells in accordance with an increased expression of their ligands, macrophage inflammatory protein-1␣, and RANTES was found in multiple sclerosis and EAE (36 -38) and was found to be diminished after different EAE treatment strategies (37,39). In our studies IL-12 alone, but not IL-18, was a potent up-regulator of CCR5 expression on MOG-specific T cells.…”

Systemic Immunomodulation of Autoimmune Disease Using MHC-Derived Recombinant TCR Ligands

“…Interestingly, expression of most chemokine receptors (CCR1, CCR2, CCR5, CCR6, CCR7 & CCR8) was moderately to strongly reduced in spinal cord tissue from RTL401-treated mice beginning at the peak of the first episode (Day 15), consistent with earlier observations [93][94][95][96][97][98]. In contrast, expression of CCR3 (Th2 associated) appeared to be uniquely enhanced during the first relapse in spinal cord tissue collected from RTL401-treated mice [84,99].…”

Monomeric Recombinant TCR Ligand Reduces Relapse Rate and Severity of Experimental Autoimmune Encephalomyelitis in SJL/J Mice through Cytokine Switch

“…10). This enhancement of CCR3 in EAE-protected mice is reminiscent of the strong up-regulation of CCR3 in BV8S2 transgenic mice successfully treated with TCR BV8S2 determinants (37). Taken together, these findings indicate that regulation of CCR expression is an important function of the RTL treatment mechanism.…”