IL-2/anti-IL-2 complexes: the resurrection of IL-2 as potential treatment for SLE-like murine chronic graft-versus-host disease?

It has been shown previously that administration of Interleukin-2 (IL-2) bound to anti-IL-2 monoclonal antibodies (IL-2 complexes) leads to a selective stimulation of T cell subsets based on the antibody used for the formation of the complexes. Moreover, the increased selectivity of IL-2 complexes prevents adverse side effects observed from administration of plain IL-2 and at the same time leads to an enhanced biological activity of this cytokine. In this study we investigated the prophylactic and therapeutic effects of two IL-2 complexes, JES6/IL-2 and S4B6/IL-2, on murine chronic Graft-versus-Host Disease (cGvHD). Therefore, we used the p→F1 model of cGvHD and induced the disease by transfer of DBA/2 lymphocytes into BDF1 mice. The IL-2 complexes were either administrated prophylactically, before disease induction, or therapeutically, 4 weeks after disease induction. We found that the JES6/IL-2 and S4B6/IL-2 have opposing effects on SLE-like symptoms in murine cGvHD. Whereas the prophylactic treatment with JES6/IL-2 had an ameliorating effect on disease symptoms accompanied by generally suppressed donor lymphocytes, prophylactic S4B6/IL-2 treatment resulted in a more severe cGvHD accompanied by a more activated donor compartment. When IL-2 complexes were administrated therapeutically (following the initiation of the disease), only S4B6/IL-2 complexes exhibited an effect and efficiently reduced disease symptoms. Our findings further suggest an important suppressive role of donor CD8+ T cells in this model of cGvHD because (i) the beneficial effect of therapeutic treatment with S4B6/IL-2 complexes depended on the presence of this population and (ii) a more aggressive cGvHD develops in the absence of these cells. Host T cells, especially CD4+ FoxP3+ regulatory T cells (Tregs), are thought to be critically involved in the control and regulation of disease driving mechanisms resulting in GvHD. To investigate the role of host T cells in graft-versus host reactions in the p→F1 model, we transferred DBA/2 lymphocytes into BDF1 mice with a restricted TCR repertoire (OT1-BDF1 and OT2-BDF1). Our findings that the transfer of DBA/2 lymphocytes (containing CD8+ T cells) leads to an acute GvHD (aGvHD) in TCR restricted (TCR oligoclonal) BDF1 mice but cGvHD in normal BDF1 mice provides further evidence for an important influence of host T cells on graft-versus-host reactions. Likely as a consequence of the greatly reduced Treg compartment in OT1-BDF1 mice, these mice develop stronger aGvHD compared to OT2-BDF1 mice. Moreover, these findings show that donor CD8+ T cells are central for the induction of acute GvHD and suggest that an insufficient control of donor CD8+ T cells by a TCR restricted host might result in aGvHD in OT1- and OT2-BDF1 mice. When DBA/2 lymphocytes depleted of CD8+ T cells are used to induce GvHD in TCR transgenic BDF1 mice, cGvHD developed, showing again more severe symptoms in OT1-BDF1 mice and milder symptoms in OT2-BDF1 mice. These results establish an important role of a diverse host T cell repertoire in the regulation of graft-versus-host reactions and the resulting GvHD