Neutralising IL-12 Activity as a Strategy for Prolonging Allograft Survival and Preventing Graft-Versus-Host Disease

1998 ◽  
Vol 43 (4) ◽  
pp. 109-111 ◽  
Author(s):  
D.J. Orr ◽  
E.M. Bolton ◽  
J.A. Bradley
Keyword(s):  
Immune Responses ◽  
Graft Versus Host Disease ◽  
Interleukin 12 ◽  
Murine Models ◽  
Allograft Survival ◽  
Host Disease ◽  
Graft Versus Host ◽  
Immunoregulatory Cytokine ◽  
Dependent Cell

Interleukin-12 (IL-12) is a key immunoregulatory cytokine which promotes the development of Thl-dependent, cell-mediated immune responses. Acute allograft rejection after organ transplantation and acute graft-versus-host disease (G VHD) after bone-marrow transplantation are generally attributed to cell-mediated immune mechanisms and, therefore, potentially susceptible to immunological intervention at the level of IL-12. Recent data from murine models of transplantation have highlighted the potential of IL-12 as a selective target for immunotherapy. Neutralising endogenous IL-12 for a brief period at the time of transplant promotes long-term deviation from a Thl to a polarised Th2 alloimmune response. This confers lasting protection from GVHD but is less effective at preventing acute rejection, possibly because Th2-dependent immune responses are also capable of effecting graft rejection.

scholarly journals Prevention of graft-versus-host disease by anti–IL-7Rα antibody

Blood ◽  
2007 ◽  
Vol 110 (8) ◽  
pp. 2803-2810 ◽  
Author(s):  
Brile Chung ◽  
Eric P. Dudl ◽  
Dullei Min ◽  
Lora Barsky ◽  
Nancy Smiley ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Murine Models ◽  
Antibody Treatment ◽  
Host Disease ◽  
Graft Versus Host

Abstract Graft-versus-host disease (GVHD) continues to be a serious complication that limits the success of allogeneic bone marrow transplantation (BMT). Using IL-7–deficient murine models, we have previously shown that IL-7 is necessary for the pathogenesis of GVHD. In the present study, we determined whether GVHD could be prevented by antibody-mediated blockade of IL-7 receptor α (IL-7Rα) signaling. C57/BL6 (H2Kb) recipient mice were lethally irradiated and underwent cotransplantation with T-cell–depleted (TCD) BM and lymph node (LN) cells from allogeneic BALB/c (H2Kd) donor mice. Following transplantation, the allogeneic BMT recipients were injected weekly with either anti–IL-7Rα antibody (100 μg per mouse per week) or PBS for 4 weeks. Anti–IL-7Rα antibody treatment significantly decreased GVHD-related morbidity and mortality compared with placebo (30% to 80%). IL-7Rα blockade resulted in the reduction of donor CD4+ or CD8+ T cells in the periphery by day 30 after transplantation. Paradoxically, the inhibition of GVHD by anti–IL-7Rα antibody treatment resulted in improved long-term thymic and immune function. Blockade of IL-7R by anti–IL-7Rα antibody resulted in elimination of alloreactive T cells, prevention of GVHD, and improvement of donor T-cell reconstitution.

scholarly journals Synergism Between Mycophenolate Mofetil and Cyclosporine in Preventing Graft-Versus-Host Disease Among Lethally Irradiated Dogs Given DLA-Nonidentical Unrelated Marrow Grafts

Blood ◽  
1998 ◽  
Vol 91 (7) ◽  
pp. 2581-2587 ◽  
Author(s):  
Cong Yu ◽  
Kristy Seidel ◽  
Richard A. Nash ◽  
H. Joachim Deeg ◽  
Brenda M. Sandmaier ◽  
...  
Keyword(s):  
Mycophenolate Mofetil ◽  
Graft Versus Host Disease ◽  
Host Disease ◽  
Graft Versus Host ◽  
Group 4 ◽  
Group 2 ◽  
Total Body ◽  
Host Tolerance ◽  
Long Term Survivors

Abstract Mycophenolate mofetil (MMF) was evaluated either alone or combined with cyclosporine (CSP) for preventing graft-versus-host disease (GVHD) in dogs given 9.2 Gy total body irradiation and DLA-nonidentical unrelated marrow grafts. Marrow autograft studies showed gut toxicity as limiting MMF side effects. Four groups were studied for GVHD prevention: six dogs in group 1 received MMF 10 mg/kg twice daily subcutaneously (SC) on days 0 to 27. They died between 8 to 28 days from infection or GVHD; survival was better than that of 72 controls given no immunosuppression (P = .04), but not different from 19 dogs given CSP. Four dogs in group 2 received MMF as described, along with CSP at 10 to 15 mg/kg twice daily on days 0 to 27. They died at 6 to 98 days from CSP-associated toxicity, weight loss, or infection. Nine dogs in group 3 received MMF SC twice daily 6 mg/kg/d for 3 days, followed by 10 mg/kg twice daily until day 27, along with CSP as described; four died between 7 to 106 days with intussusception, infection, or GVHD, and five became long-term survivors. Six dogs in group 4 received shortened MMF (21 days) and reduced doses of CSP given through day 100. Three died with GVHD or infection between days 38 to 119, and three became long-term survivors. Results support the notion of synergism between MMF and CSP, as evidenced by stable graft-host tolerance in greater than 50% of dogs.

scholarly journals Granzyme B is not required for regulatory T cell–mediated suppression of graft-versus-host disease

Blood ◽  
2010 ◽  
Vol 115 (9) ◽  
pp. 1669-1677 ◽  
Author(s):  
Sheng F. Cai ◽  
Xuefang Cao ◽  
Anjum Hassan ◽  
Todd A. Fehniger ◽  
Timothy J. Ley
Keyword(s):  
Immune Responses ◽  
Treg Cell ◽  
Graft Versus Host Disease ◽  
Granzyme B ◽  
Target Organ Damage ◽  
Organ Damage ◽  
Treg Cells ◽  
Host Disease ◽  
Graft Versus Host

Abstract Regulatory T (Treg) cells can suppress a wide variety of immune responses, including antitumor and alloimmune responses. The mechanisms by which Treg cells mediate their suppressive effects depend on the context of their activation. We previously reported that granzyme B is important for Treg cell–mediated suppression of antitumor immune responses. We therefore hypothesized that granzyme B may likewise be important for suppression of graft-versus-host disease (GVHD). We found that allogeneic mismatch induces the expression of granzyme B in mixed lymphocyte reactions and in a model of graft-versus-host disease (GVHD). However, wild-type and granzyme B–deficient Treg cells were equally able to suppress effector T (Teff) cell proliferation driven by multiple stimuli, including allogeneicantigen-presenting cells. Surprisingly, adoptive transfer of granzyme B–deficient Treg cells prevented GVHD lethality, suppressed serum cytokine production in vivo, and prevented target organ damage. These data contrast strikingly with our previous study, which demonstrated that granzyme B plays a nonredundant role in Treg cell–mediated suppression of antitumor responses. Taken together, these findings suggest that targeting specific Treg cell–suppressive mechanisms, such as granzyme B, may be therapeutically beneficial for segregating GVHD and graft-versus-tumor immune responses.

scholarly journals Acute graft-versus-host disease: a bench-to-bedside update

Blood ◽  
2014 ◽  
Vol 124 (3) ◽  
pp. 363-373 ◽  
Author(s):  
Shernan G. Holtan ◽  
Marcelo Pasquini ◽  
Daniel J. Weisdorf
Keyword(s):  
Small Molecules ◽  
Graft Versus Host Disease ◽  
Host Disease ◽  
Multiple Modalities ◽  
Graft Versus Host ◽  
The Past ◽  
Prevention And Treatment ◽  
Near Future ◽  
Acute Graft

Abstract Over the past 5 years, many novel approaches to early diagnosis, prevention, and treatment of acute graft-versus-host disease (aGVHD) have been translated from the bench to the bedside. In this review, we highlight recent discoveries in the context of current aGVHD care. The most significant innovations that have already reached the clinic are prophylaxis strategies based upon a refinement of our understanding of key sensors, effectors, suppressors of the immune alloreactive response, and the resultant tissue damage from the aGVHD inflammatory cascade. In the near future, aGVHD prevention and treatment will likely involve multiple modalities, including small molecules regulating immunologic checkpoints, enhancement of suppressor cytokines and cellular subsets, modulation of the microbiota, graft manipulation, and other donor-based prophylaxis strategies. Despite long-term efforts, major challenges in treatment of established aGVHD still remain. Resolution of inflammation and facilitation of rapid immune reconstitution in those with only a limited response to corticosteroids is a research arena that remains rife with opportunity and urgent clinical need.

scholarly journals Uva1 Phototherapy in the Management of Sclerodermatous Graft-Versus-Host Disease (Gvhd): a report of two cases / Uva1 fototerapija u lečenju sklerodermatoznog oblika hronične Gvhd: Prikaz dva slučaja

2009 ◽  
Vol 1 (4) ◽  
pp. 147-152 ◽  
Author(s):  
Hiva Fassihi ◽  
Kamran Iqbal ◽  
Trish Garibaldinos ◽  
Robert Sarkany ◽  
Julia Scarisbrick ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Skin Diseases ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Allogeneic Hsct ◽  
Graft Versus Host ◽  
Uva1 Phototherapy ◽  
Matched Sibling

Abstract Chronic graft-versus-host disease (GVHD) is a frequent complication after allogeneic hematopoietic stem cell transplantation (HSCT). Approximately 10% of patients with GVHD develop sclerodermatous changes, which can cause significant morbidity and are often refractory to standard systemic immunosuppression. We present two cases of sclerodermatous GVHD. The first is a 39-year-old man, who had a matched sibling, undergoing allogeneic HSCT for severe aplastic anemia. The second patient is a 7-year-old boy, who had an allogeneic HSCT from his HLA-identical mother for acute myeloid leukemia (AML). Both patients presented with widespread sclerotic changes, resulting in joint contractures and significant functional difficulties. Studies have shown UVA1 phototherapy to be a promising and well tolerated treatment modality in patients with sclerotic skin diseases. Both of our patients were treated with UVA1, which resulted in a significant skin softening, improvement in joint mobility and quality of life. UVA1 appears to be an effective treatment for refractory sclerodermatous GVHD; however, long-term clinical studies in larger groups are needed to accurately evaluate its efficacy and safety.

scholarly journals Simple, Reproducible, and Efficient Clinical Grading System for Murine Models of Acute Graft-versus-Host Disease

2018 ◽  
Vol 9 ◽  
Author(s):  
Sina Naserian ◽  
Mathieu Leclerc ◽  
Allan Thiolat ◽  
Caroline Pilon ◽  
Cindy Le Bret ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Grading System ◽  
Murine Models ◽  
Host Disease ◽  
Graft Versus Host ◽  
Clinical Grading ◽  
Acute Graft
Sign in / Sign up

Export Citation Format

Share Document