Tracking ex vivo-expanded CD4+CD25+ and CD8+CD25+ regulatory T cells after infusion to prevent donor lymphocyte infusion-induced lethal acute graft-versus-host.

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Tracking ex vivo-expanded CD4+CD25+ and CD8+CD25+ regulatory T cells after infusion to prevent donor lymphocyte infusion-induced lethal acute graft-versus-host disease Guliang Xia, Mike Kovochich, Robert L. Truitt, Bryon D. Johnson Biology of Blood and Marrow Transplantation Volume 10, Issue 11, Pages 748-760 (November 2004) DOI: 10.1016/j.bbmt.2004.07.004 Copyright © 2004 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 1 Fresh and ex vivo-expanded CD25+ T cells were suppressive in vitro. Fresh CD25+ cells, CD25+ cells activated by alloAgs, IL-2, anti-CD3/CD28 mAbs, or combinations of these stimuli (A and B), as well as ex vivo-expanded CD3+CD25+ or CD4+, CD8+, and CD4−CD8− subsets (C), were assayed for suppressive activity in MLR assays. In some experiments (D), exogenous IL-2 was added directly to the assays. All curves are expressed as percentage of control MLR and represent the combined average values of 10 to 15 individual experiments. The raw data values for the control MLRs ranged from 10 to 15 × 104 CPM. Biology of Blood and Marrow Transplantation 2004 10, 748-760DOI: (10.1016/j.bbmt.2004.07.004) Copyright © 2004 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 2 Fresh and ex vivo-expanded CD25+ cells could be detected long-term after adoptive transfer into syngeneic or allogeneic nude mice. The peripheral blood of syngeneic B6 or allogeneic BALB/c nude recipient mice given fresh Thy1.1+ B6.PL CD25+ cells (A-D) or ex vivo-expanded CD4+CD25+ cells (C and D) was analyzed at various time points for the presence of infused cells (A and C) and for the maintenance of CD25 expression on infused cells (B and D). At 24 week after transfer, all mice were killed, and the peripheral blood (PB), spleen (SP), and lymph node (LN) were analyzed by flow cytometric analysis of gated lymphocytes. The results are the combined data of syngeneic B6 nude recipients given fresh (n = 5; A-D) or ex vivo-expanded CD4+CD25+ cells (n = 5; C and D) or NK cell-depleted allogeneic BALB/c nude recipients infused with fresh (n = 5; C and D) or ex vivo-expanded CD4+CD25+ cells (n = 5; C and D). Biology of Blood and Marrow Transplantation 2004 10, 748-760DOI: (10.1016/j.bbmt.2004.07.004) Copyright © 2004 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 3 CD25−/− BM chimeras or normal BM chimeras depleted of CD25+ cells developed lethal GVHD after DLI. The survival (A) and average body weights (B) for CD25+/+ (n = 10), CD25+/− (n = 10), or CD25−/− (n = 15) BM chimeras were monitored after DLI with 5 × 106 CD3+CD25− T cells. In (C) and (D), untreated or in vivo CD25-depleted CD25+/+ chimeras were given DLI with whole splenocytes (undepleted DLI) or CD25-depleted splenocytes (CD25-depleted DLI) at doses of 3 × 107 (C) or 6 × 107 (D) cells. In the CD25 depletion experiments, a total of 11 to 12 mice for each experimental DLI group were analyzed, representing the combined data from 3 independent experiments. The CD25-depleted, no-DLI control group in (C) and (D) consisted of 3 mice. BMT controls (CD25+/+, CD25+/−, and CD25−/−), composed of 3 to 5 animals for each group without DLI therapy, were followed up long-term but not shown on Figure 3. Biology of Blood and Marrow Transplantation 2004 10, 748-760DOI: (10.1016/j.bbmt.2004.07.004) Copyright © 2004 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 4 Adoptively transferred fresh or ex vivo-expanded donor CD25+ cells suppressed the development of DLI-induced GVHD in CD25−/− BM chimeras. Survival graphs (A and B) and body weight curves (C and D) are shown for CD25−/− chimeras given fresh (A and C) or ex vivo-expanded CD25+ cells (B and D) at the time of DLI (5 × 106 CD25− T cells given 28 days after transplantation). Fresh and ex vivo-expanded CD25+ cells were given at CD25−/CD25+ cell ratios of 1:1 (n = 9 mice per group) or 2:1 (n = 11 for fresh; n = 8 for expanded). Controls consisted of CD25−/− BM chimeras given DLI without co-infusion of CD25+ cells (n = 15). Biology of Blood and Marrow Transplantation 2004 10, 748-760DOI: (10.1016/j.bbmt.2004.07.004) Copyright © 2004 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 5 CD8+CD25+ cells weakly suppressed the development of DLI-induced GVHD in CD25−/− BM chimeras. Survival (A) and body weights (B) were monitored for CD25−/− chimeras co-infused with DLI and 5 × 106 (n = 10) or 2.5 × 106 (n = 9) ex vivo-expanded CD8+CD25+ cells on day 28 after BMT. Controls consisted of CD25−/− chimeras given DLI only (n = 15). Biology of Blood and Marrow Transplantation 2004 10, 748-760DOI: (10.1016/j.bbmt.2004.07.004) Copyright © 2004 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 6 Long-term persistence of fresh or ex vivo-expanded CD4+CD25+ cells given to suppress GVHD in vivo. Fresh Thy1.1+ B6.PL CD25+ cells or ex vivo-expanded CD4+CD25+ cells were tracked for in vivo persistence (A) and maintenance of CD25 expression (B) after co-infusion with DLI into CD25−/− Thy1.2+ BM chimeras. Flow cytometric analysis of gated lymphocytes in the peripheral blood (PB), spleens (SP), and lymph nodes (LN) was performed at the indicated time points. Biology of Blood and Marrow Transplantation 2004 10, 748-760DOI: (10.1016/j.bbmt.2004.07.004) Copyright © 2004 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 7 Ex vivo-expanded CD4+CD25+ cells persisted and proliferated only in CD25−/−, but not CD25+/+, BM chimeras after co-infusion with DLI cells. Ex vivo-expanded CD4+CD25+ cells were tracked for in vivo persistence after co-infusion with DLI into CD25−/− or CD25+/+ Thy1.2+ BM chimeras. Biology of Blood and Marrow Transplantation 2004 10, 748-760DOI: (10.1016/j.bbmt.2004.07.004) Copyright © 2004 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 8 Ex vivo-expanded CD8+CD25+ cells quickly disappeared after infusion to suppress GVHD in vivo. Ex vivo-expanded CD8+CD25+ cells were tracked for in vivo persistence after co-infusion with DLI into CD25−/− Thy1.2+ BM chimeras at 1:1 or 2:1 DLI/Treg ratios. Biology of Blood and Marrow Transplantation 2004 10, 748-760DOI: (10.1016/j.bbmt.2004.07.004) Copyright © 2004 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 9 Only Treg cells that maintained CD25 expression in vivo were suppressive in vitro. Persisting Thy1.1+ Treg subsets (CD4+CD25+, CD4+25−, and CD8+) were isolated by flow cytometric sorting from the spleen (SP) and Lymph node (LN) of syngeneic nude mice 6 months after adoptive transfer (A) or from the SP and LN of DLI-treated CD25−/− chimeras 15 weeks after infusion (B). The reisolated cells were then assayed for suppressive activity in MLR assays. All curves are expressed as percentage of control MLR and represent the combined average values of 6 to 9 individual experiments. The raw data values for the control MLRs ranged from 8 to 10 × 104 CPM. Biology of Blood and Marrow Transplantation 2004 10, 748-760DOI: (10.1016/j.bbmt.2004.07.004) Copyright © 2004 American Society for Blood and Marrow Transplantation Terms and Conditions