scholarly journals Treatment of moderate/severe acute graft-versus-host disease after allogeneic bone marrow transplantation: an analysis of clinical risk features and outcome

Blood ◽  
1990 ◽  
Vol 75 (4) ◽  
pp. 1024-1030 ◽  
Author(s):  
D Weisdorf ◽  
R Haake ◽  
B Blazar ◽  
W Miller ◽  
P McGlave ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Graft Versus Host ◽  
Grade Ii ◽  
Acute Graft

We have analyzed the long term outcome of 197 patients who were treated for grade II to IV acute graft-versus-host disease (GVHD) following histocompatible allogeneic bone marrow transplantation (BMT). Of 469 recipients of sibling donor allografts performed at our center between January, 1979 and October, 1987, 197 patients (42%) developed greater than or equal to grade II acute GVHD at a median of 38 days (range 9 to 98 days) post-BMT. After treatment with corticosteroids (n = 160) or other immunosuppressive therapies (n = 37), 72 patients (41% +/- 8%; 95% confidence interval [CI]) achieved complete and continuing resolution of acute GVHD after a median of 21 days of therapy. Sixty- one patients required additional immunosuppressive therapy with high dose methylprednisolone, antithymocyte globulin (ATG)/steroids, or other therapies because of refractory or progressive symptoms of acute GVHD. Seven of these 61 patients eventually obtained complete and continuing remission after 13 to 57 days (median 50) of secondary treatment. The overall rate of chronic GVHD was 70% +/- 16%; 95% CI following grade II to IV acute GVHD. Twenty-five of the 197 patients never developed chronic GVHD, resulting in a Kaplan-Meier projection of 30% +/- 8% (95% CI) cure of moderate/severe acute GVHD. Analysis of clinical features associated with complete response (CR) to acute GVHD therapy identified more favorable responses to therapy in patients without either liver or skin involvement, patients with acute lymphoblastic leukemia, and donor/recipient pairs other than male patients with female donors. Older recipient age was not associated with more resistance to GVHD treatment. CR to GVHD treatment was associated with significantly better 5-year survival: 51% +/- 14% versus 32% +/- 11% for patients with therapy resistant acute GVHD (P = .004). GVHD was a major contributing cause of death in 49 of the 90 patients who died and was often complicated by infection or interstitial pneumonitis. Control of acute GVHD through immunosuppressive therapy did not affect the risk of leukemic relapse after transplantation.

scholarly journals Treatment of moderate/severe acute graft-versus-host disease after allogeneic bone marrow transplantation: an analysis of clinical risk features and outcome

Blood ◽  
1990 ◽  
Vol 75 (4) ◽  
pp. 1024-1030 ◽  
Author(s):  
D Weisdorf ◽  
R Haake ◽  
B Blazar ◽  
W Miller ◽  
P McGlave ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Graft Versus Host ◽  
Grade Ii ◽  
Acute Graft

Abstract We have analyzed the long term outcome of 197 patients who were treated for grade II to IV acute graft-versus-host disease (GVHD) following histocompatible allogeneic bone marrow transplantation (BMT). Of 469 recipients of sibling donor allografts performed at our center between January, 1979 and October, 1987, 197 patients (42%) developed greater than or equal to grade II acute GVHD at a median of 38 days (range 9 to 98 days) post-BMT. After treatment with corticosteroids (n = 160) or other immunosuppressive therapies (n = 37), 72 patients (41% +/- 8%; 95% confidence interval [CI]) achieved complete and continuing resolution of acute GVHD after a median of 21 days of therapy. Sixty- one patients required additional immunosuppressive therapy with high dose methylprednisolone, antithymocyte globulin (ATG)/steroids, or other therapies because of refractory or progressive symptoms of acute GVHD. Seven of these 61 patients eventually obtained complete and continuing remission after 13 to 57 days (median 50) of secondary treatment. The overall rate of chronic GVHD was 70% +/- 16%; 95% CI following grade II to IV acute GVHD. Twenty-five of the 197 patients never developed chronic GVHD, resulting in a Kaplan-Meier projection of 30% +/- 8% (95% CI) cure of moderate/severe acute GVHD. Analysis of clinical features associated with complete response (CR) to acute GVHD therapy identified more favorable responses to therapy in patients without either liver or skin involvement, patients with acute lymphoblastic leukemia, and donor/recipient pairs other than male patients with female donors. Older recipient age was not associated with more resistance to GVHD treatment. CR to GVHD treatment was associated with significantly better 5-year survival: 51% +/- 14% versus 32% +/- 11% for patients with therapy resistant acute GVHD (P = .004). GVHD was a major contributing cause of death in 49 of the 90 patients who died and was often complicated by infection or interstitial pneumonitis. Control of acute GVHD through immunosuppressive therapy did not affect the risk of leukemic relapse after transplantation.

Blockade of CD134 (OX40)-CD134L interaction ameliorates lethal acute graft-versus-host disease in a murine model of allogeneic bone marrow transplantation

Blood ◽  
2000 ◽  
Vol 95 (7) ◽  
pp. 2434-2439 ◽  
Author(s):  
Nobuhiro Tsukada ◽  
Hisaya Akiba ◽  
Tetsuji Kobata ◽  
Yoshifusa Aizawa ◽  
Hideo Yagita ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Graft Versus Host Disease ◽  
Murine Model ◽  
Marrow Transplantation ◽  
Acute Gvhd ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Graft Versus Host ◽  
Acute Graft

Expression of CD134 (OX40) on activated CD4+ T cells has been observed in acute graft-versus-host disease (GVHD) after human and rat allogeneic bone marrow transplantation (BMT). We investigated the role of interaction between CD134 and CD134 ligand (CD134L) in a murine model of acute GVHD by using a newly established monoclonal antibody (mAb) against murine CD134L. Acute GVHD was induced by transfer of bone marrow cells and spleen cells into lethally irradiated recipients in a parent (C57BL/6) to first filial generation (C57BL/6 crossed with DBA/2) BMT. Administration of anti-CD134L mAb significantly reduced the lethality of acute GVHD and other manifestations of the disease, such as loss of body weight, hunched posture, diarrhea, and patchy alopecia. The survival rate 80 days after BMT in mice treated with the mAb was about 70%, whereas all mice treated with control antibodies died within 43 days. Histologic examinations revealed that inflammatory changes in target organs such as the liver, gut, and skin were also ameliorated in mice treated with the mAb compared with control mice. An in vitro assay of T-cell proliferation showed a marked hyporesponsiveness to host alloantigen in samples from mice treated with anti-CD134L mAb. In addition, low levels of interferon γ and transiently elevated levels of interleukin 4 and IgE in serum samples were found in mice treated with anti-CD134L mAb. These results suggest that CD134-CD134L interactions have an important role in the pathogenesis of acute GVHD.

Blockade of CD134 (OX40)-CD134L interaction ameliorates lethal acute graft-versus-host disease in a murine model of allogeneic bone marrow transplantation

Blood ◽  
2000 ◽  
Vol 95 (7) ◽  
pp. 2434-2439 ◽  
Author(s):  
Nobuhiro Tsukada ◽  
Hisaya Akiba ◽  
Tetsuji Kobata ◽  
Yoshifusa Aizawa ◽  
Hideo Yagita ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Graft Versus Host Disease ◽  
Murine Model ◽  
Marrow Transplantation ◽  
Acute Gvhd ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Graft Versus Host ◽  
Acute Graft

Abstract Expression of CD134 (OX40) on activated CD4+ T cells has been observed in acute graft-versus-host disease (GVHD) after human and rat allogeneic bone marrow transplantation (BMT). We investigated the role of interaction between CD134 and CD134 ligand (CD134L) in a murine model of acute GVHD by using a newly established monoclonal antibody (mAb) against murine CD134L. Acute GVHD was induced by transfer of bone marrow cells and spleen cells into lethally irradiated recipients in a parent (C57BL/6) to first filial generation (C57BL/6 crossed with DBA/2) BMT. Administration of anti-CD134L mAb significantly reduced the lethality of acute GVHD and other manifestations of the disease, such as loss of body weight, hunched posture, diarrhea, and patchy alopecia. The survival rate 80 days after BMT in mice treated with the mAb was about 70%, whereas all mice treated with control antibodies died within 43 days. Histologic examinations revealed that inflammatory changes in target organs such as the liver, gut, and skin were also ameliorated in mice treated with the mAb compared with control mice. An in vitro assay of T-cell proliferation showed a marked hyporesponsiveness to host alloantigen in samples from mice treated with anti-CD134L mAb. In addition, low levels of interferon γ and transiently elevated levels of interleukin 4 and IgE in serum samples were found in mice treated with anti-CD134L mAb. These results suggest that CD134-CD134L interactions have an important role in the pathogenesis of acute GVHD.

scholarly journals Quantitative assessment of posttransplant host-specific interleukin-2- secreting T-helper cell precursors in patients with and without acute graft-versus-host disease after allogeneic HLA-identical sibling bone marrow transplantation

Blood ◽  
1993 ◽  
Vol 81 (3) ◽  
pp. 841-848
Author(s):  
T Nierle ◽  
D Bunjes ◽  
R Arnold ◽  
H Heimpel ◽  
M Theobald
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Interleukin 2 ◽  
T Helper ◽  
Graft Versus Host ◽  
Grade Ii ◽  
Acute Graft

Recent studies in mice and humans have emphasized an important contribution of host-reactive minor histocompatibility antigen (mH)- specific lymphokine-secreting donor T-helper cells (Th) for the induction of acute graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT). By using limiting dilution (LD) and clonal specificity analyses, we investigated in 14 patients with and without acute GVHD after non-T-depleted HLA-identical sibling BMT whether posttransplant host-reactive mH-specific interleukin-2 (IL-2)- secreting Th are involved in the development of clinically significant acute GVHD and the establishment of tolerance. At different time intervals posttransplant (I, days 0 through 45; II, days 45 through 90; III, days 90 through 180), host-specific IL-2-secreting Th-precursors (Th-p) were quantitatively assessed in six patients during clinically apparent grade II-III acute GVHD. Frequencies of responding Th-p ranged from 1/13,000 to 1 4,000. The presence of host-specific Th-p was significantly correlated with the development of grade II-III acute GVHD (P = .0003 by Fisher's exact test). The detectability of host- specific Th-p preceded the clinical onset of grade II-III acute GVHD. Host-specific Th-p were no longer detectable after the clinical resolution of grade II-III acute GVHD. No subsequent chronic GVHD was observed in these patients. However, prolonged occurrence of host- specific Th-p was accompanied by clinically persisting acute GVHD and the onset of secondary chronic GVHD. In patients with no acute GVHD (grade 0) (n = 7) and grade I (n = 1) acute GVHD, host-specific Th-p were not detectable at all. We conclude that host-reactive Th are critically involved in the development and maintenance of acute GVHD and may contribute to the establishment of tolerance after genotypically HLA-identical sibling BMT.

scholarly journals Quantitative assessment of posttransplant host-specific interleukin-2- secreting T-helper cell precursors in patients with and without acute graft-versus-host disease after allogeneic HLA-identical sibling bone marrow transplantation

Blood ◽  
1993 ◽  
Vol 81 (3) ◽  
pp. 841-848 ◽  
Author(s):  
T Nierle ◽  
D Bunjes ◽  
R Arnold ◽  
H Heimpel ◽  
M Theobald
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Interleukin 2 ◽  
T Helper ◽  
Graft Versus Host ◽  
Grade Ii ◽  
Acute Graft

Abstract Recent studies in mice and humans have emphasized an important contribution of host-reactive minor histocompatibility antigen (mH)- specific lymphokine-secreting donor T-helper cells (Th) for the induction of acute graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT). By using limiting dilution (LD) and clonal specificity analyses, we investigated in 14 patients with and without acute GVHD after non-T-depleted HLA-identical sibling BMT whether posttransplant host-reactive mH-specific interleukin-2 (IL-2)- secreting Th are involved in the development of clinically significant acute GVHD and the establishment of tolerance. At different time intervals posttransplant (I, days 0 through 45; II, days 45 through 90; III, days 90 through 180), host-specific IL-2-secreting Th-precursors (Th-p) were quantitatively assessed in six patients during clinically apparent grade II-III acute GVHD. Frequencies of responding Th-p ranged from 1/13,000 to 1 4,000. The presence of host-specific Th-p was significantly correlated with the development of grade II-III acute GVHD (P = .0003 by Fisher's exact test). The detectability of host- specific Th-p preceded the clinical onset of grade II-III acute GVHD. Host-specific Th-p were no longer detectable after the clinical resolution of grade II-III acute GVHD. No subsequent chronic GVHD was observed in these patients. However, prolonged occurrence of host- specific Th-p was accompanied by clinically persisting acute GVHD and the onset of secondary chronic GVHD. In patients with no acute GVHD (grade 0) (n = 7) and grade I (n = 1) acute GVHD, host-specific Th-p were not detectable at all. We conclude that host-reactive Th are critically involved in the development and maintenance of acute GVHD and may contribute to the establishment of tolerance after genotypically HLA-identical sibling BMT.

The primacy of the gastrointestinal tract as a target organ of acute graft-versus-host disease: rationale for the use of cytokine shields in allogeneic bone marrow transplantation

Blood ◽  
2000 ◽  
Vol 95 (9) ◽  
pp. 2754-2759 ◽  
Author(s):  
Geoffrey R. Hill ◽  
James L. M. Ferrara
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Graft Versus Host Disease ◽  
Marrow Transplantation ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Gi Tract ◽  
Host Disease ◽  
Graft Versus Host ◽  
Acute Graft

Acute graft-versus-host disease (GVHD), the major complication of allogeneic bone marrow transplantation (BMT), limits the application of this curative but toxic therapy. Studies of inflammatory pathways involved in GVHD in animals have shown that the gastrointestinal (GI) tract plays a major role in the amplification of systemic disease. Damage to the GI tract increases the translocation of inflammatory stimuli such as endotoxin, which promotes further inflammation and additional GI tract damage. The GI tract is therefore critical to the propagation of the “cytokine storm” characteristic of acute GVHD. Experimental approaches to the prevention of GVHD include reducing the damage to the GI tract by fortification of the GI mucosal barrier through novel “cytokine shields” such as IL-11 or keratinocyte growth factor. Such strategies have reduced GVHD while preserving a graft-versus-leukemia effect in animal models, and they now deserve formal testing in carefully designed clinical trials.

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