CD4(+)CD25(+) immunoregulatory T Cells: new therapeutics for graft-versus-host disease - PubMed (original) (raw)
CD4(+)CD25(+) immunoregulatory T Cells: new therapeutics for graft-versus-host disease
José L Cohen et al. J Exp Med. 2002.
Abstract
CD4(+)CD25(+) immunoregulatory T cells play a pivotal role in preventing organ-specific autoimmune diseases and in tolerance induction to allogeneic organ transplants. We investigated whether these cells could also control graft-versus-host disease (GVHD), the main complication after allogeneic hematopoietic stem cell transplantation (HSCT). Here, we show that the few CD4(+)CD25(+) T cells naturally present in the transplant regulate GVHD because their removal from the graft dramatically accelerates this disease. Furthermore, the addition of freshly isolated CD4(+)CD25(+) T cells at time of grafting significantly delays or even prevents GVHD. Ex vivo-expanded CD4(+)CD25(+) regulatory T cells obtained after stimulation by allogeneic recipient-type antigen-presenting cells can also modulate GVHD. Thus, CD4(+)CD25(+) regulatory T cells represent a new therapeutic tool for controlling GVHD in allogeneic HSCT. More generally, these results outline the tremendous potential of regulatory T cells as therapeutics.
Figures
Figure 1.
CD4+CD25+ regulatory T cells naturally present in the transplant modulate GVHD. Lethally irradiated (B6 × D2)F1 mice were grafted with semiallogeneic B6 BM cells supplemented with either 10 × 106 B6 T cells (○; n = 10) or 10 × 106 CD25-depleted B6 T cells (•; n = 10). Cumulative results from two independent experiments are shown. Kaplan-Meier survival curves were established for each group with the indicated P-values.
Figure 2.
Prevention of GVHD by the addition of fresh CD4+CD25+ regulatory T cells. Lethally irradiated mice were grafted with allogeneic BM cells supplemented with either 10 × 106 T cells (○; n = 5) or 10 × 106 T cells and 5 × 106 freshly isolated CD4+CD25+ T cells (▴; n = 4). (A) Survival of (B6 × D2)F1 recipients transplanted with semiallogeneic B6 cells. (B) Survival of C3H recipients transplanted with fully allogeneic BALB/c cells. Kaplan-Meier survival curves were established with the indicated P-values.
Figure 3.
Phenotypic characterization and in vitro properties of ex vivo–expanded CD4+CD25+ T cells. (A) 0.2 × 106 B6 (○) or 5.5 × 106 BALB/c (•) purified CD4+CD25+CD62Lhigh T cells were stimulated with IL-2 and irradiated splenocytes from (B6 × D2)F1 or C3H mice, respectively. The graph depicts the expansion of living cells. (B) Flow cytometry analyses for the expression of CD4, CD25, and CD62L (inset) on total cells and CD4+CD25+CD62Lhigh T cells after cell sorting (fresh) and after 2 wk of stimulation with allogeneic irradiated splenocytes and IL-2 (cultured). (C) CD4+CD25+CD62Lhigh T cells from BALB/c mice were stimulated with C3H APCs (left) or B6 APCs (right). After 2 wk of culture, T cells were restimulated with either the same allogeneic APCs (•) or third-party allogeneic APCs (○; B6 on the left and C3H on the right). Proliferation was assessed after 2, 2.5, or 3 d of stimulation. In both assays, T cell proliferation to third-party allogeneic APCs in the presence of IL-2, and the one obtained in the culture without APCs in the presence of IL-2, was comparable and below 10,000 cpm. (D) A constant number of BALB/c CD25-depleted cells (effector T cells) was stimulated by C3H APCs. Cells were cocultured with different numbers of BALB/c-expanded CD4+CD25+ T cells to assess their suppressive activity at different ratios between regulatory T cells and effector cells. Inhibition of the proliferation of effector T cells as compared with the culture without regulatory T cells (10,125 cpm) is shown.
Figure 3.
Phenotypic characterization and in vitro properties of ex vivo–expanded CD4+CD25+ T cells. (A) 0.2 × 106 B6 (○) or 5.5 × 106 BALB/c (•) purified CD4+CD25+CD62Lhigh T cells were stimulated with IL-2 and irradiated splenocytes from (B6 × D2)F1 or C3H mice, respectively. The graph depicts the expansion of living cells. (B) Flow cytometry analyses for the expression of CD4, CD25, and CD62L (inset) on total cells and CD4+CD25+CD62Lhigh T cells after cell sorting (fresh) and after 2 wk of stimulation with allogeneic irradiated splenocytes and IL-2 (cultured). (C) CD4+CD25+CD62Lhigh T cells from BALB/c mice were stimulated with C3H APCs (left) or B6 APCs (right). After 2 wk of culture, T cells were restimulated with either the same allogeneic APCs (•) or third-party allogeneic APCs (○; B6 on the left and C3H on the right). Proliferation was assessed after 2, 2.5, or 3 d of stimulation. In both assays, T cell proliferation to third-party allogeneic APCs in the presence of IL-2, and the one obtained in the culture without APCs in the presence of IL-2, was comparable and below 10,000 cpm. (D) A constant number of BALB/c CD25-depleted cells (effector T cells) was stimulated by C3H APCs. Cells were cocultured with different numbers of BALB/c-expanded CD4+CD25+ T cells to assess their suppressive activity at different ratios between regulatory T cells and effector cells. Inhibition of the proliferation of effector T cells as compared with the culture without regulatory T cells (10,125 cpm) is shown.
Figure 3.
Phenotypic characterization and in vitro properties of ex vivo–expanded CD4+CD25+ T cells. (A) 0.2 × 106 B6 (○) or 5.5 × 106 BALB/c (•) purified CD4+CD25+CD62Lhigh T cells were stimulated with IL-2 and irradiated splenocytes from (B6 × D2)F1 or C3H mice, respectively. The graph depicts the expansion of living cells. (B) Flow cytometry analyses for the expression of CD4, CD25, and CD62L (inset) on total cells and CD4+CD25+CD62Lhigh T cells after cell sorting (fresh) and after 2 wk of stimulation with allogeneic irradiated splenocytes and IL-2 (cultured). (C) CD4+CD25+CD62Lhigh T cells from BALB/c mice were stimulated with C3H APCs (left) or B6 APCs (right). After 2 wk of culture, T cells were restimulated with either the same allogeneic APCs (•) or third-party allogeneic APCs (○; B6 on the left and C3H on the right). Proliferation was assessed after 2, 2.5, or 3 d of stimulation. In both assays, T cell proliferation to third-party allogeneic APCs in the presence of IL-2, and the one obtained in the culture without APCs in the presence of IL-2, was comparable and below 10,000 cpm. (D) A constant number of BALB/c CD25-depleted cells (effector T cells) was stimulated by C3H APCs. Cells were cocultured with different numbers of BALB/c-expanded CD4+CD25+ T cells to assess their suppressive activity at different ratios between regulatory T cells and effector cells. Inhibition of the proliferation of effector T cells as compared with the culture without regulatory T cells (10,125 cpm) is shown.
Figure 4.
Regulation of GVHD by the addition of expanded CD4+CD25+ regulatory T cells. At the end of the culture (days 15 and 28 for regulatory T cells from BALB/c and B6 mice, respectively), expanded regulatory T cells were tested for their capacity to control GVHD. (A) Lethally irradiated mice were grafted with allogeneic BM cells supplemented with either 10 × 106 fresh T cells (○; n = 5 per group) or 10 × 106 fresh T cells and 7 × 106 expanded CD4+CD25+ T cells (▴; n = 5 per group). For both genetic combinations, the addition of expanded CD4+CD25+ T cells statistically increased the survival of mice. (B) Lethally irradiated B6 mice were grafted with BALB/c BM cells and 10 × 106 fresh BABL/c T cells (○, GVHD control group; n = 5) supplemented with 7 × 106 expanded regulatory T cells derived from cultured CD4+CD25+ T cells stimulated by C3H splenocytes (▪, nonspecific regulatory T cells; n = 5), or B6 splenocytes (•, specific regulatory T cells; n = 5). The difference in survival between the GVHD control group and mice receiving nonspecific CD4+CD25+ T cells is statistically insignificant. When statistically significant, Kaplan-Meier survival curves were established with the indicated P-values.
Figure 4.
Regulation of GVHD by the addition of expanded CD4+CD25+ regulatory T cells. At the end of the culture (days 15 and 28 for regulatory T cells from BALB/c and B6 mice, respectively), expanded regulatory T cells were tested for their capacity to control GVHD. (A) Lethally irradiated mice were grafted with allogeneic BM cells supplemented with either 10 × 106 fresh T cells (○; n = 5 per group) or 10 × 106 fresh T cells and 7 × 106 expanded CD4+CD25+ T cells (▴; n = 5 per group). For both genetic combinations, the addition of expanded CD4+CD25+ T cells statistically increased the survival of mice. (B) Lethally irradiated B6 mice were grafted with BALB/c BM cells and 10 × 106 fresh BABL/c T cells (○, GVHD control group; n = 5) supplemented with 7 × 106 expanded regulatory T cells derived from cultured CD4+CD25+ T cells stimulated by C3H splenocytes (▪, nonspecific regulatory T cells; n = 5), or B6 splenocytes (•, specific regulatory T cells; n = 5). The difference in survival between the GVHD control group and mice receiving nonspecific CD4+CD25+ T cells is statistically insignificant. When statistically significant, Kaplan-Meier survival curves were established with the indicated P-values.
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References
- Thomas, E.D., R. Storb, R.A. Clift, A. Fefer, L. Johnson, P.E. Neiman, K.G. Lerner, H. Glucksberg, and C.D. Buckner. 1975. Bone-marrow transplantation. N. Engl. J. Med. 292:895–902. - PubMed
- Martin, P.J., J.A. Hansen, C.D. Buckner, J.E. Sanders, H.J. Deeg, P. Stewart, F.R. Appelbaum, R. Clift, A. Fefer, R.P. Witherspoon, et al. 1985. Effects of in vitro depletion of T cells in HLA-identical allogeneic marrow grafts. Blood. 66:664–672. - PubMed
- Mackall, C.L., and R.E. Gress. 1997. Thymic aging and T-cell regeneration. Immunol. Rev. 160:91–102. - PubMed
- Horowitz, M.M., R.P. Gale, P.M. Sondel, J.M. Goldman, J. Kersey, H.J. Kolb, A.A. Rimm, O. Ringden, C. Rozman, B. Speck, et al. 1990. Graft-versus-leukemia reactions after bone marrow transplantation. Blood. 75:555–562. - PubMed
- Storb, R., H.J. Deeg, M. Pepe, F. Appelbaum, C. Anasetti, P. Beatty, W. Bensinger, R. Berenson, C.D. Buckner, R. Clift, et al. 1989. Methotrexate and cyclosporine versus cyclosporine alone for prophylaxis of graft-versus-host disease in patients given HLA-identical marrow grafts for leukemia: long-term follow-up of a controlled trial. Blood. 73:1729–1734. - PubMed
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