scholarly journals Prevention of graft-versus-host disease (GVHD) by elimination of recipient-reactive donor T cells with recombinant toxins that target the interleukin 2 (IL-2) receptor

1999 ◽  
Vol 23 (2) ◽  
pp. 137-144 ◽  
Author(s):  
DT Harris ◽  
D Sakiestewa ◽  
C Lyons ◽  
RJ Kreitman ◽  
I Pastan
Keyword(s):  
T Cells ◽  
Graft Versus Host Disease ◽  
Interleukin 2 ◽  
Host Disease ◽  
Graft Versus Host ◽  
Donor T Cells

Prevention of Marrow Graft Rejection Without Induction of Graft-Versus-Host Disease by a Cytotoxic T-Cell Clone That Recognizes Recipient Alloantigens

Blood ◽  
1998 ◽  
Vol 91 (11) ◽  
pp. 4038-4044 ◽  
Author(s):  
Yoichiro Kusunoki ◽  
Wei Chen ◽  
Paul J. Martin
Keyword(s):  
T Cells ◽  
Graft Versus Host Disease ◽  
Graft Rejection ◽  
Interleukin 2 ◽  
Cytotoxic T Cell ◽  
Marrow Graft ◽  
Host Disease ◽  
Graft Versus Host ◽  
T Cell Clone ◽  
Donor T Cells

In allogeneic marrow transplantation, donor T cells that recognize recipient alloantigens prevent rejection but also cause graft-versus-host disease (GVHD). To evaluate whether the ability to prevent marrow graft rejection could be dissociated from the ability to cause GVHD, we generated a panel of four different CD8 cytotoxic T-lymphocyte clones specific for H2d alloantigens. Three of the clones caused no overt toxicity when as many as 20 × 106 cells were infused intravenously into irradiated H2d-positive recipients, and one clone caused acute lethal toxicity within 1 to 3 days after transferring 10 × 106cells into H2d-positive recipients. One clone that did not cause toxicity was able to prevent rejection of (C57BL/6J × C3H/HeJ)F1 marrow in 800 cGy-irradiated (BALB/cJ × C57BL/6J)F1 recipients without causing GVHD. Large numbers of cells and exogenously administered interleukin-2 were required to prevent rejection. These results with different CD8 clones suggest that GVHD and prevention of rejection could be separable effects mediated by distinct populations of donor T cells that recognize recipient alloantigens.

Prevention of Marrow Graft Rejection Without Induction of Graft-Versus-Host Disease by a Cytotoxic T-Cell Clone That Recognizes Recipient Alloantigens

Blood ◽  
1998 ◽  
Vol 91 (11) ◽  
pp. 4038-4044 ◽  
Author(s):  
Yoichiro Kusunoki ◽  
Wei Chen ◽  
Paul J. Martin
Keyword(s):  
T Cells ◽  
Graft Versus Host Disease ◽  
Graft Rejection ◽  
Interleukin 2 ◽  
Cytotoxic T Cell ◽  
Marrow Graft ◽  
Host Disease ◽  
Graft Versus Host ◽  
T Cell Clone ◽  
Donor T Cells

Abstract In allogeneic marrow transplantation, donor T cells that recognize recipient alloantigens prevent rejection but also cause graft-versus-host disease (GVHD). To evaluate whether the ability to prevent marrow graft rejection could be dissociated from the ability to cause GVHD, we generated a panel of four different CD8 cytotoxic T-lymphocyte clones specific for H2d alloantigens. Three of the clones caused no overt toxicity when as many as 20 × 106 cells were infused intravenously into irradiated H2d-positive recipients, and one clone caused acute lethal toxicity within 1 to 3 days after transferring 10 × 106cells into H2d-positive recipients. One clone that did not cause toxicity was able to prevent rejection of (C57BL/6J × C3H/HeJ)F1 marrow in 800 cGy-irradiated (BALB/cJ × C57BL/6J)F1 recipients without causing GVHD. Large numbers of cells and exogenously administered interleukin-2 were required to prevent rejection. These results with different CD8 clones suggest that GVHD and prevention of rejection could be separable effects mediated by distinct populations of donor T cells that recognize recipient alloantigens.

Selective T-cell subset ablation demonstrates a role for T1 and T2 cells in ongoing acute graft-versus-host disease: a model system for the reversal of disease

Blood ◽  
2001 ◽  
Vol 98 (12) ◽  
pp. 3367-3375 ◽  
Author(s):  
Jinli Liu ◽  
Britt E. Anderson ◽  
Marie E. Robert ◽  
Jennifer M. McNiff ◽  
Stephen G. Emerson ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Interleukin 2 ◽  
Late Time ◽  
Clinical Effects ◽  
Host Disease ◽  
Graft Versus Host ◽  
Donor T Cells ◽  
T1 And T2

Abstract Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality of allogeneic stem cell transplantation. Strategies to control GVHD while maintaining graft versus leukemia (GVL) include herpes simplex virus thymidine kinase (HSV-tk) gene transduction of donor T cells followed by treatment with ganciclovir (GCV). Alternatively, GVHD and GVL may be mediated by distinct processes. In this regard, whether cytokine polarization occurs and to what degrees various subsets of cytokine-producing T cells mediate GVHD or GVL has been an active area of research using cytokine or cytokine antibody infusion or genetically deficient mice. This study takes a different approach that allows simultaneous investigation into both the mechanisms underlying GVHD reactions and the efficacy of HSV-tk suicide gene-based T-cell deletion. A source of donor T cells, splenocytes from mice transgenic for HSV-tk controlled by elements of either the interleukin-2 (IL-2) or IL-4 promoters (IL-2-tk and IL-4-tk, respectively) was used, thus allowing investigation into the roles of T1 and T2 cells in ongoing GVHD reactions. To assess treatment rather than prevention of GVHD, GCV was started at peak disease. Remarkably, treatment at this late time point rescued mice from the clinical effects of GVHD caused by T cells expressing either transgene. Thus, both T1 and T2 cells play an important role in clinical GVHD in a minor histocompatibility antigen-mismatched setting. In addition, because clinical disease was reversible even at its maximum, these observations provide controlled evidence that this strategy of treating ongoing GVHD could be effective clinically.

Post‐transplant cyclophosphamide limits reactive donor T cells and delays the development of graft‐versus‐host disease in a humanised mouse model

Immunology ◽  
2021 ◽  
Author(s):  
Sam Raj Adhikary ◽  
Peter Cuthbertson ◽  
Leigh Nicholson ◽  
Katrina M. Bird ◽  
Chloe Sligar ◽  
...  
Keyword(s):  
T Cells ◽  
Mouse Model ◽  
Graft Versus Host Disease ◽  
Host Disease ◽  
Graft Versus Host ◽  
Post Transplant ◽  
Donor T Cells

scholarly journals IL-6 dysregulation originates in dendritic cells and mediates graft-versus-host disease via classical signaling

Blood ◽  
2019 ◽  
Vol 134 (23) ◽  
pp. 2092-2106 ◽  
Author(s):  
Andrew N. Wilkinson ◽  
Karshing Chang ◽  
Rachel D. Kuns ◽  
Andrea S. Henden ◽  
Simone A. Minnie ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Graft Versus Host Disease ◽  
Host Disease ◽  
Graft Versus Host ◽  
Key Points ◽  
Donor T Cells ◽  
Principal Source

Key Points DCs are the principal source of IL-6 dysregulation after alloSCT. IL-6–dependent GVHD is driven by classical signaling of IL-6R on donor T cells but is regulated by trans signaling.

scholarly journals Interleukin-2 inhibits graft-versus-host disease-promoting activity of CD4+ cells while preserving CD4- and CD8-mediated graft-versus-leukemia effects

Blood ◽  
1994 ◽  
Vol 83 (9) ◽  
pp. 2560-2569 ◽  
Author(s):  
M Sykes ◽  
MW Harty ◽  
GL Szot ◽  
DA Pearson
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Interleukin 2 ◽  
Cell Subset ◽  
Spleen Cells ◽  
Host Disease ◽  
Graft Versus Host ◽  
T Cell Subset ◽  
Graft Versus Leukemia

Abstract We have recently shown that a short course of high-dose interleukin-2 (IL-2) can markedly inhibit the graft-versus-host disease (GVHD)- promoting activity of donor CD4+ T cells. The difficulty in dissociating GVHD-promoting from graft-versus-leukemia (GVL) effects of alloreactive donor T cells currently prevents clinical bone marrow transplantation (BMT) from fulfilling its full potential. To test the capacity of IL-2 treatment to promote such a dissociation, we have developed a new murine transplantable acute myelogenous leukemia model using a class II major histocompatibility complex-positive BALB/c Moloney murine leukemia virus-induced promonocytic leukemia, 2B-4–2. BALB/c mice receiving 2.5 x 10(5) 2B-4–2 cells intravenously 1 week before irradiation and syngeneic BMT died from leukemia within 2 to 4 weeks after BMT. Administration of syngeneic spleen cells and/or a 2.5- day course of IL-2 treatment alone did not inhibit leukemic mortality. In contrast, administration of non-T-cell-depleted fully allogeneic B10 (H-2b) spleen cells and T-cell-depleted B10 marrow led to a significant delay in leukemic mortality in IL-2-treated mice. In these animals GVHD was inhibited by IL-2 treatment. GVL effects were mediated entirely by donor CD4+ and CD8+ T cells. Remarkably, IL-2 administration did not diminish the magnitude of the GVL effect of either T-cell subset. This was surprising, because CD4-mediated GVHD was inhibited in the same animals in which CD4-mediated GVL effects were not reduced by IL-2 treatment. These results suggest a novel mechanism by which GVHD and GVL effects of a single unprimed alloreactive T-cell subset can be dissociated; different CD4 activities promote GVHD and GVL effects, and the former, but not the latter activities are inhibited by treatment with IL-2.

Selective Depletion of Alloreacting CD25+ Cells from Stem Cell Allografts Can Reduce Acute Graft-Versus-Host Disease Following Matched Related Donor Transplantation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 426-426
Author(s):  
Scott R. Solomon ◽  
Thao Tran ◽  
Charles S. Carter ◽  
Nancy Hensel ◽  
Laura Wisch ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Cell Transplant ◽  
Host Disease ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis ◽  
Donor T Cells ◽  
Related Donor

Abstract Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality after allogeneic stem cell transplant (SCT), especially in older patients. We previously showed that host-reactive donor T cells are selectively depleted (SD) from an allograft ex vivo, following a short co-culture of donor cells with irradiated T cell stimulators from the recipient and subsequent treatment with an anti-CD25 immunotoxin. We report a pilot study to test the hypothesis that GVHD could be decreased in a cohort of elderly patients receiving SD allografts from HLA-identical sibling donors. Sixteen patients, median age 65 years (range 51–73), with advanced hematologic malignancies were transplanted following reduced-intensity conditioning with fludarabine and either cyclophosphamide (n=5), melphalan (n=5), or busulfan (n=6). Cyclosporine was used as the only additional GVHD prophylaxis. SD allografts contained a median CD34 dose of 4.5x106/kg (range 3.5–7.3) and an SD CD3 dose of 1.0x108/kg (range 0.2–1.5). Fifteen patients achieved sustained engraftment. The helper T lymphocyte precursor (HTLp) frequency assay demonstrated depletion of host-reactive donor T cells in 9/11 cases tested from a mean of 1/182,089 to 1/822,354 (mean 5.5-fold depletion), while third party responses were conserved. Kaplan-Meier estimates of probability of grade II-IV and grade III-IV acute GVHD were lower than those seen in a historical control group of patients receiving cyclosporine alone for GVHD prophylaxis (35±13% vs. 57±10%, p=0.34) and (7±6% vs. 38±6%, p=0.05), respectively. Of note, the two patients who developed visceral (gut ± liver) GVHD showed ineffective allodepletion by HTLp (figure). Chronic GVHD occurred in five of 14 evaluable patients. At a median follow-up of 212 days (range 60 – 690), seven of sixteen patients remain alive and in remission. Relapse deaths occurred in four patients (refractory AML [2], therapy-related MDS [1], and CMML [1]). Non-relapse mortality in this high-risk cohort of patients included graft failure [1], GVHD [2], infection [1], and myocardial infarction [1]. In summary, CD25-directed allodepletion of stem cell allografts can reduce clinically relevant acute GVHD following matched related donor transplantation. Figure Figure

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