Tolerance to Cyclosporin A-Induced Autologous Graft-Versus-Host Disease Is Mediated by a CD4+CD25+ Subset of Recent Thymic Emigrants

Abstract

Our previous studies revealed that both the autoeffector and immunoregulatory T cells in cyclosporin A (CSA)-induced autologous graft-vs-host disease are recent thymic emigrants (RTEs). The autoeffector cells appear in and are released from the thymus during the first week of CSA treatment, whereas the immunoregulatory thymocytes appear during the second week but are not released until several days after cessation of CSA treatment. In the present study, the antigenic phenotypes of these functional T cell subsets were determined by immunomagnetic separation and flow immunocytometric analysis. During CSA wk 1, the autoeffector T cells in both the thymus and lymph node (LN) expressed a CD4+8+ double-positive (DP) phenotype, after which those in the LN became CD8 single positive (SP). Timed thymectomy experiments confirmed that the CD8-SP autoeffector T cells in LN originated from these DP RTEs. During CSA wk 2, the immunoregulatory thymocytes also displayed a DP phenotype. However, they were not exported to the periphery until several days after CSA treatment had been interrupted and they had acquired a CD4-SP phenotype. In LN, these immunoregulatory RTEs expressed the CD25+ marker characteristic of anergic/suppressor T cells. Cell separation and mixing experiments demonstrated that the autoeffector T cells persist in LN after cessation of CSA treatment, but their activity is not detectable in the presence of recently exported CD4+ T cells. Hence, the results indicate that tolerance to CSA-induced autologous graft-vs-host disease is actively mediated by CD25+CD4+ RTEs that suppress the function of CD8 autoeffector T cells.

Rapamycin, not cyclosporine, permits thymic generation and peripheral preservation of CD4+CD25+FoxP3+ T cells

“…In agreement with our findings, CsA treatment of newborn mice was found to cause autoimmune diseases similar to those observed following neonatal thymectomy, which also has a detrimental effect on T REG homeostasis. 38 Moreover, our data fit with the observations that CsA decreases the expansion of adoptively transferred FoxP3 þ T cells, 39,40 whereas rapamycin treatment spares T REG in vivo. 39,41 Decreased FoxP3 levels have been associated with GVHD in several studies.…”

Second autologous transplant with cyclosporin/interferon α-induced graft versus host disease for patients who have failed first-line consolidation

“…Recent evidence from an animal model has demonstrated the presence of peripheral autocytotoxic T cells in the first 7 days following CsA treatment and persisting for up to 2 weeks following the cessation of CsA therapy. 32 However, autoregulatory T cells only appear peripherally after cessation of CsA therapy, suggesting that early upregulation of Class II expression using IFN may be more beneficial. Recent studies have suggested a role for nonmyeloablative SCT for patients relapsing post first autologous transplant; 33 however, few patients will have an eligible donor and an antilymphoma effect has not yet been established.…”

CD4+ T Cells Prevent Skin Autoimmunity During Chronic Autologous Graft-Versus-Host-Disease

“…In mice, CsA is necessary for the development of autoGVHD, as animals receiving ASCT alone almost never develop pathological clinical symptoms. Recent studies have brought new insights into the mechanisms of action of CsA following ASCT by demonstrating that CsA is able to delay the emigration of CD4+ 25+ T-regulatory cells without affecting the departure of other T-cell subsets (8). It is thus tempting to speculate that, when CsA treatment is stopped, mature CD8+ and CD4+ 25-T cells can be activated and become effector cells leading to autoGVHD, the more so because T-regulatory cells still reside in the thymus.…”

“…Second, CsA is able to interfere with the thymic differentiation of T-cell subsets and may alter the kinetics of recovery of effector vs. regulatory cells. In this respect, Wu and Goldschneider have shown that thymus emigration of CD4+ 25+ regulatory T cells in CsA-treated mice occurs several days after the emigration of mature naïve autoreactive T cells (8). This delay in CD4CD25 T-cell recovery may lead to a transient lack of down-regulatory mechanisms, allowing activation of effector T cells and development of autoGVHD.…”

“…Acute autoGVHD may be fatal (6). Chronic autoGVHD may affect the gastro-intestinal tract or the skin (7); and (iv) development of the clinical symptoms of autoGVHD is owing to the activation in the tissues of autoreactive effector T cells which are under the control of CD4+ downregulatory T cells (T reg) (8).…”