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. 2008 Aug 15;112(4):1515-21.
doi: 10.1182/blood-2007-11-125542. Epub 2008 Apr 14.

"V体育ios版" Extracorporeal photopheresis reverses experimental graft-versus-host disease through regulatory T cells

Erin Gatza  1 , Clare E Rogers, Shawn G Clouthier, Kathleen P Lowler, Isao Tawara, Chen Liu, Pavan Reddy, James L M Ferrara
Affiliations

"V体育官网入口" Extracorporeal photopheresis reverses experimental graft-versus-host disease through regulatory T cells

Erin Gatza et al. Blood. .

Abstract (V体育2025版)

Extracorporeal photopheresis (ECP), a technique that exposes isolated white blood cells to photoactivatable 8-methoxypsoralen and ultraviolet A radiation, is used clinically to treat cutaneous T-cell lymphoma and immune-mediated diseases such as graft-versus-host disease (GVHD). ECP is thought to control these diseases in part through direct induction of lymphocyte apoptosis, but its effects on the immune system beyond apoptosis remain poorly characterized. We have developed a novel method for incorporating ECP treatment into well-established and clinically relevant murine models of GVHD to examine its effects during an ongoing immune response. We demonstrate that the transfer of cells treated with ECP reverses established GVHD by increasing donor regulatory T cells and indirectly reducing the number of donor effector lymphocytes that themselves had never been exposed to psoralen and ultraviolet A radiation. VSports手机版.

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"VSports注册入口" Figures

Figure 1
Figure 1
ECP-treated cells reduce GVHD and mortality after allogeneic BMT. (A) Survival and clinical GVHD scores after BMT. C3H.SW mice received syngeneic (C3H.SW; □, n = 15) or allogeneic (B6-Ly5.2) BM transplant followed by 4 weekly infusions of diluent (♦, n = 26) or of B6→C3H.SW splenocytes that were untreated (▵, n = 19) or treated with ECP (formula image, n = 34); formula image versus ▵ or ♦, *P < .004. (B) Histopathology scores 56 days after BMT (n = 8-20 per group); ▩ versus ▨, *P < .03. (C) Spleen reconstitution with donor lymphocytes (B6-Ly5.2) 56 days after BMT (n = 6-8 per group); ▩ versus ■, *P < .02. (D) Survival and clinical GVHD scores after haploidentical BMT. B6D2F1 mice received syngeneic (B6D2F1; □, n = 6) or allogeneic (B6-Ly5.2) BMT followed by 4 weekly infusions of diluent (♦, n = 18) or of B6→B6D2F1 splenocytes that were treated with ECP (formula image, n = 13); formula image versus ♦, *P < .02. Data are means (± SD) pooled from at least 2 independent experiments.
Figure 2
Figure 2
ECP-treated splenocytes reduce CD8+IFN-γ+ effector T cells in vivo. C3H.SW recipient mice received 5.0 × 106 bone marrow and 106 T cells from syngeneic (C3H.SW) or allogeneic (B6-Ly5.2) donors on day 0 followed by infusion of B6→C3H.SW ECP-treated cells on day 7. IFN-γ production by donor CD8+ effector cells was measured 96 hours later. (A) Representative flow cytometry data of unseparated splenocytes gated on whole-cell scatter. Percentage of donor (CD45.1+) CD8+ T cells in R4 (left) or producing IFN-γ (right) indicated. (B) Numbers of donor CD8+IFN-γ+ cells per spleen. ▩ versus ■, *P < .05. Data are means (± SD) pooled from 3 independent experiments (n = 9-20 per group).
Figure 3
Figure 3
ECP-treated splenocytes reduce allogeneic T-cell responses and increase Foxp3 expression in vitro. (A,B) B6-Ly5.2 responder T cells were incubated at a 10:1 ratio with syngeneic B6 (□) or allogeneic B6D2F1 (■) stimulator DCs for 60 hours in the presence of untreated (▨) or ECP-treated (▩) B6→B6D2F1 splenocytes at a 1:1 ratio with responders. (A) Numbers of responder CD8+IFN-γ+ cells per well (left) and proliferation of bulk responder cells (right); ▩ versus ■ or ▨, *P < .05. (B) Percentage of CD4+Foxp3+ cells; ▩ versus ■ or ▨, *P < .05. (C) Proliferation of fresh MLR cultures containing 10 B6-Ly5.2 responder T cells per B6D2F1 stimulator DC after cells harvested from panels A-B were added at a 1:1 ratio with responders. − indicates nothing added; +, cells added from primary cultures as colored in panels A,B; ▩ versus ■ or ▨, *P < .05. Syngeneic control groups had low background proliferation (< 2.0 × 103 cpm) that was unaffected by addition of cells from panel A,B (data not shown). Data are means (± SD) pooled from at least 2 independent experiments (n = 6-9 wells per group).
Figure 4
Figure 4
Infusion of ECP-treated splenocytes increases donor Treg after allogeneic BMT. B6 and C3H.SW (CD45.2+Thy1.2+) recipient mice received 5.0 × 106 T cell–depleted B6-Ly5.2 (CD45.1+Thy1.2+) bone marrow and 106 B6-Thy1.1 (CD45.2+Thy1.1+) T cells followed by infusion of ECP-treated B6→C3H.SW splenocytes. (A) Gating strategy for Tregs using representative day-35 MLN data. CD4+Foxp3+ or CD4+CD25+Foxp3+ cells were gated on whole cell scatter followed by segregation into CD45.1+Thy1.1− BM or CD45.1−Thy1.1+ T-cell inoculum-derived cells. (B) Total numbers of CD4+CD25+Foxp3+ cells after infusion of ECP-treated cells from second BMT cohort; ▩ versus ■, *P < .02. At day 11, mice had received 1 infusion of ECP-treated cells, and at day 35 they had received 4 infusions. (C,D) Numbers of donor CD4+CD25+Foxp3+ cells from the BM and T-cell grafts in the spleen and MLN 11 and 35 days after BMT, respectively. (C) Allo plus diluent versus allo plus ECP, ■, P < .03; (D) allo plus diluent versus allo plus ECP, ▩, P = .04. Bars represent means (± SD). Data pooled from 3 to 4 independent experiments (n = 12-20/group).
Figure 5
Figure 5
Tregs are required for reversal of GVHD by ECP. (A-C) C3H.SW recipient mice received syngeneic (C3H.SW; □, n = 3) or allogeneic (B6-Ly5.2) BM transplant and 4 weekly infusions of ECP-treated B6→C3H.SW splenocytes (gray circle, n = 12) or diluent (♦, n = 8), as described in “Bone marrow transplantation” and “ECP treatment.” All BM transplant recipients were injected intraperitoneally with 0.5 mg CD25-depleting mAb (PC61) on day 1 and 0.1 mg on days 8, 15, 22, and 29 after BMT. (A) Number of CD4+Foxp3+ Tregs 56 days after BMT (n = 3-4 per group). Bars represent means (± SD). (B) Survival. (C) Clinical GVHD scores.
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References

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