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

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.

Download Full-text

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

Blood ◽

10.1182/blood.v91.11.4038 ◽

1998 ◽

Vol 91 (11) ◽

pp. 4038-4044 ◽

Cited By ~ 5

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.

Download Full-text

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

Bone Marrow Transplantation ◽

10.1038/sj.bmt.1701535 ◽

1999 ◽

Vol 23 (2) ◽

pp. 137-144 ◽

Cited By ~ 37

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

Download Full-text

Attenuation of graft-versus-host disease and graft rejection by ex vivo immunotoxin elimination of alloreactive T cells in an H-2 haplotype disparate mouse combination

Blood ◽

10.1182/blood.v83.1.288.bloodjournal831288 ◽

1994 ◽

Vol 83 (1) ◽

pp. 288-298 ◽

Cited By ~ 1

Author(s):

M Cavazzana-Calvo ◽

JL Stephan ◽

S Sarnacki ◽

S Chevret ◽

C Fromont ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Graft Versus Host Disease ◽

Graft Rejection ◽

Ex Vivo ◽

Interleukin 2 ◽

In Vivo Model ◽

Host Disease ◽

Graft Versus Host

A mouse anti-interleukin-2 receptor A-chain-specific PC61-immunotoxin (PC61-IT) strongly inhibited a primary mixed lymphocyte culture and major histocompatibility complex (MHC)-restricted cytotoxicity. The allodepleted T cells retained their proliferative and cytotoxic capacities in response to third-party stimulation, showing that PC61-IT specifically deleted recipient antigen-specific T-cell clones from the donor mouse. The ability of this specific allodepletion to prevent graft-versus-host disease (GVHD) and graft rejection was investigated in vivo. IT-depleted, activated parental T lymphocytes (C3H/eB) were intravenously injected into lethally irradiated CDF1 mice. GVHD was evaluated after 6 days on the severity of gut lesions. PC61-IT-treated cells significantly reduced both donor T-cell infiltration and acceleration of epithelial renewal (a sensitive index of gut damage) as compared with those for the corresponding untreated controls. The effect of selective allo-depletion on prevention of GVHD and graft rejection was further studied after MHC-haploincompatible bone marrow (BM) transplantation. A significant increase in survival was observed in mice receiving 2 x 10(6) T-cell-depleted BM cells and 0.5 x 10(6) PC61-IT-treated T cells, because one-third were alive without GVHD (and with stable full or partial engraftment) after 100 days, whereas all the mice infused with BM and sham-treated T cells died within 80 days from GVHD, and all the mice infused with BM cells alone rejected grafts. Furthermore, specific tolerance in chimeras towards donor cells could be shown. These results as observed in an experimental in vivo model corroborate previous results obtained in vitro in humans and lead us to consider the use of this selective allodepletion in human BM transplant from donors other than identical familial siblings.

Download Full-text

Irradiated Donor Leukocytes Promote Engraftment of Allogeneic Bone Marrow in Major Histocompatibility Complex Mismatched Recipients Without Causing Graft-Versus-Host Disease

Blood ◽

10.1182/blood.v94.9.3222 ◽

1999 ◽

Vol 94 (9) ◽

pp. 3222-3233 ◽

Cited By ~ 42

Author(s):

Edmund K. Waller ◽

Alan M. Ship ◽

Stephen Mittelstaedt ◽

Timothy W. Murray ◽

Richard Carter ◽

...

Keyword(s):

Bone Marrow ◽

T Cells ◽

Major Histocompatibility Complex ◽

Graft Versus Host Disease ◽

Graft Rejection ◽

Allogeneic Bone ◽

Host Disease ◽

Graft Versus Host ◽

Histocompatibility Complex ◽

Donor T Cells

Abstract Graft rejection in allogeneic bone marrow transplantation (BMT) can occur when donor and recipient are mismatched at one or more major histocompatibility complex (MHC) loci. Donor T cells can prevent graft rejection, but may cause fatal graft-versus-host disease (GVHD). We tested whether irradiation of allogeneic donor lymphocytes would preserve their graft-facilitating activity while inhibiting their potential for GVHD. Infusions of irradiated allogeneic T cells did not cause GVHD in MHC-mismatched SJL → (SJL × C57BL6) F1, C57BL6 → B10.RIII, and C57BL6 → B10.BR mouse donor → recipient BMT pairs. The 60-day survival among MHC-mismatched transplant recipients increased from 2% (BM alone) to up to 75% among recipients of BM plus irradiated allogeneic splenocytes. Optimal results were obtained using 50 × 106 to 75 × 106 irradiated donor splenocytes administered in multiple injections from day −1 to day +1. Recipients of an equal number of nonirradiated MHC-mismatched donor splenocytes uniformly died of acute GVHD. The graft facilitating activity of the irradiated allogeneic splenocytes was mediated by donor T cells. Irradiation to 7.5 Gy increased nuclear NFκB in T cells and their allospecific cytotoxicity. Irradiated T cells survived up to 3 days in the BM of MHC-mismatched recipients without proliferation. Recipients of irradiated allogeneic splenocytes and allogeneic BM had stable donor-derived hematopoiesis without a significant representation of donor splenocytes in the T-cell compartment. Irradiated allogeneic T cells thus represent a form of cellular immunotherapy with time-limited biologic activity in vivo that can facilitate allogeneic BMT without causing GVHD.

Download Full-text

Irradiated Donor Leukocytes Promote Engraftment of Allogeneic Bone Marrow in Major Histocompatibility Complex Mismatched Recipients Without Causing Graft-Versus-Host Disease

Blood ◽

10.1182/blood.v94.9.3222.421k06_3222_3233 ◽

1999 ◽

Vol 94 (9) ◽

pp. 3222-3233 ◽

Cited By ~ 1

Author(s):

Edmund K. Waller ◽

Alan M. Ship ◽

Stephen Mittelstaedt ◽

Timothy W. Murray ◽

Richard Carter ◽

...

Keyword(s):

Bone Marrow ◽

T Cells ◽

Major Histocompatibility Complex ◽

Graft Versus Host Disease ◽

Graft Rejection ◽

Allogeneic Bone ◽

Host Disease ◽

Graft Versus Host ◽

Histocompatibility Complex ◽

Donor T Cells

Graft rejection in allogeneic bone marrow transplantation (BMT) can occur when donor and recipient are mismatched at one or more major histocompatibility complex (MHC) loci. Donor T cells can prevent graft rejection, but may cause fatal graft-versus-host disease (GVHD). We tested whether irradiation of allogeneic donor lymphocytes would preserve their graft-facilitating activity while inhibiting their potential for GVHD. Infusions of irradiated allogeneic T cells did not cause GVHD in MHC-mismatched SJL → (SJL × C57BL6) F1, C57BL6 → B10.RIII, and C57BL6 → B10.BR mouse donor → recipient BMT pairs. The 60-day survival among MHC-mismatched transplant recipients increased from 2% (BM alone) to up to 75% among recipients of BM plus irradiated allogeneic splenocytes. Optimal results were obtained using 50 × 106 to 75 × 106 irradiated donor splenocytes administered in multiple injections from day −1 to day +1. Recipients of an equal number of nonirradiated MHC-mismatched donor splenocytes uniformly died of acute GVHD. The graft facilitating activity of the irradiated allogeneic splenocytes was mediated by donor T cells. Irradiation to 7.5 Gy increased nuclear NFκB in T cells and their allospecific cytotoxicity. Irradiated T cells survived up to 3 days in the BM of MHC-mismatched recipients without proliferation. Recipients of irradiated allogeneic splenocytes and allogeneic BM had stable donor-derived hematopoiesis without a significant representation of donor splenocytes in the T-cell compartment. Irradiated allogeneic T cells thus represent a form of cellular immunotherapy with time-limited biologic activity in vivo that can facilitate allogeneic BMT without causing GVHD.

Download Full-text

Attenuation of graft-versus-host disease and graft rejection by ex vivo immunotoxin elimination of alloreactive T cells in an H-2 haplotype disparate mouse combination

Blood ◽

10.1182/blood.v83.1.288.288 ◽

1994 ◽

Vol 83 (1) ◽

pp. 288-298 ◽

Cited By ~ 68

Author(s):

M Cavazzana-Calvo ◽

JL Stephan ◽

S Sarnacki ◽

S Chevret ◽

C Fromont ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Graft Versus Host Disease ◽

Graft Rejection ◽

Ex Vivo ◽

Interleukin 2 ◽

In Vivo Model ◽

Host Disease ◽

Graft Versus Host

Abstract A mouse anti-interleukin-2 receptor A-chain-specific PC61-immunotoxin (PC61-IT) strongly inhibited a primary mixed lymphocyte culture and major histocompatibility complex (MHC)-restricted cytotoxicity. The allodepleted T cells retained their proliferative and cytotoxic capacities in response to third-party stimulation, showing that PC61-IT specifically deleted recipient antigen-specific T-cell clones from the donor mouse. The ability of this specific allodepletion to prevent graft-versus-host disease (GVHD) and graft rejection was investigated in vivo. IT-depleted, activated parental T lymphocytes (C3H/eB) were intravenously injected into lethally irradiated CDF1 mice. GVHD was evaluated after 6 days on the severity of gut lesions. PC61-IT-treated cells significantly reduced both donor T-cell infiltration and acceleration of epithelial renewal (a sensitive index of gut damage) as compared with those for the corresponding untreated controls. The effect of selective allo-depletion on prevention of GVHD and graft rejection was further studied after MHC-haploincompatible bone marrow (BM) transplantation. A significant increase in survival was observed in mice receiving 2 x 10(6) T-cell-depleted BM cells and 0.5 x 10(6) PC61-IT-treated T cells, because one-third were alive without GVHD (and with stable full or partial engraftment) after 100 days, whereas all the mice infused with BM and sham-treated T cells died within 80 days from GVHD, and all the mice infused with BM cells alone rejected grafts. Furthermore, specific tolerance in chimeras towards donor cells could be shown. These results as observed in an experimental in vivo model corroborate previous results obtained in vitro in humans and lead us to consider the use of this selective allodepletion in human BM transplant from donors other than identical familial siblings.

Download Full-text

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 ◽

10.1182/blood.v98.12.3367 ◽

2001 ◽

Vol 98 (12) ◽

pp. 3367-3375 ◽

Cited By ~ 40

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.

Download Full-text