scholarly journals Increased P2X7 expression in the gastrointestinal tract and skin in a humanised mouse model of graft-versus-host disease

2020 ◽  
Vol 134 (2) ◽  
pp. 207-223 ◽  
Author(s):  
Peter Cuthbertson ◽  
Sam R. Adhikary ◽  
Nicholas J. Geraghty ◽  
Thomas V. Guy ◽  
Amirazin Hadjiashrafi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Graft Versus Host Disease ◽  
Mononuclear Cells ◽  
Early Stage ◽  
Human Peripheral Blood ◽  
Quantitative Polymerase Chain Reaction ◽  
Haematopoietic Stem Cell ◽  
Host Disease ◽  
Graft Versus Host ◽  
Nsg Mice

Abstract Background: Allogeneic haematopoietic stem cell transplantation (HSCT) is a curative therapy for blood cancers; but results in the development of graft-versus-host disease (GVHD) in up to 70% of recipients. During GVHD, tissue damage results in ATP release into the extracellular compartment activating P2X7 on antigen-presenting cells, leading to the release of pro-inflammatory cytokines and subsequent activation of donor T cells. Therefore, the aim of the present study was to examine murine (m) P2rx7 and human (h) P2RX7 gene expression in GVHD target organs of humanised mice, and further characterise disease impact in these organs. Methods: NOD-scid IL2Rγnull (NSG) mice were injected with human peripheral blood mononuclear cells (hu-PBMC-NSG mice) or phosphate-buffered saline (PBS, control). Leucocytes were assessed by flow cytometry; gene expression was measured by quantitative polymerase chain reaction (qPCR), and tissue sections examined by histology. Results: Compared with control mice, hu-PBMC-NSG mice had increased mP2rx7 and mP2rx4 expression in the duodenum, ileum and skin. hP2RX7 was expressed in all tissues examined. hu-PBMC-NSG mice also displayed increased mReg3g expression in the duodenum and ileum, despite limited histological gut GVHD. hu-PBMC-NSG mice showed histological evidence of GVHD in the skin, liver and lung. Compared with control mice, hu-PBMC-NSG mice displayed increased ear swelling. Conclusion: Combined data revealed that P2rx7 is up-regulated in gut and skin GVHD and that P2RX7 is present in target tissues of GVHD, corresponding to human leucocyte infiltration. Data also reveal increased mReg3g expression and ear swelling in hu-PBMC-NSG mice, offering new measurements of early-stage gut GVHD and skin GVHD, respectively.

scholarly journals Bone marrow transplantation and approaches to avoid graft-versus-host disease (GVHD)

2005 ◽  
Vol 360 (1461) ◽  
pp. 1747-1767 ◽  
Author(s):  
Bruce R Blazar ◽  
William J Murphy
Keyword(s):  
Graft Versus Host Disease ◽  
Opportunistic Infections ◽  
Haematopoietic Stem Cell ◽  
Generation Process ◽  
Host Disease ◽  
Immune Effector ◽  
Effector Cells ◽  
Graft Versus Host ◽  
Donor T Cells ◽  
Donor Graft

Haematopoietic stem cell transplantation (HSCT) offers promise for the treatment of haematological and immune disorders, solid tumours, and as a tolerance inducing regimen for organ transplantation. Allogeneic HSCTs engraftment requires immunosuppression and the anti-tumour effects are dependent upon the immune effector cells that are contained within or generated from the donor graft. However, significant toxicities currently limit its efficacy. These problems include: (i) graft-versus-host disease (GVHD) in which donor T cells attack the recipient resulting in multi-organ attack and morbidity, (ii) a profound period of immune deficiency following HSCT, and (iii) donor graft rejection. Currently available methods to prevent or treat GVHD with systemic immunosuppression can lead to impaired immune recovery, increased opportunistic infections, and higher relapse rates. This review will provide an overview of GVHD pathophysiology and discuss the roles of various cells, pathways, and factors in the GVHD generation process and in the preservation of graft-versus-tumour effects. Variables that need to be taken into consideration in attempting to extrapolate preclinical results to the clinical paradigm will be highlighted.

Individual HLA alleles and risk of graft-versus-host disease after haematopoietic stem cell transplantation from HLA-identical siblings

Biologia ◽  
2020 ◽  
Vol 75 (11) ◽  
pp. 2045-2052
Author(s):  
Ivana Shawkatová ◽  
Eva Bojtárová ◽  
Monika Kováčová ◽  
Kristína Klučková ◽  
Mária Kušíková ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Haematopoietic Stem Cell Transplantation ◽  
Haematopoietic Stem Cell ◽  
Host Disease ◽  
Hla Alleles ◽  
Graft Versus Host

scholarly journals Role of Natural Killer Cells in Intravenous Immunoglobulin–Induced Graft-versus-Host Disease Inhibition in NOD/LtSz-scidIL2rg−/− (NSG) Mice

2015 ◽  
Vol 21 (5) ◽  
pp. 821-828 ◽  
Author(s):  
Joëlle Gregoire-Gauthier ◽  
François Fontaine ◽  
Lionel Benchimol ◽  
Simon Nicoletti ◽  
Silvia Selleri ◽  
...  
Keyword(s):  
Natural Killer Cells ◽  
Natural Killer ◽  
Intravenous Immunoglobulin ◽  
Graft Versus Host Disease ◽  
Killer Cells ◽  
Host Disease ◽  
Graft Versus Host ◽  
Nsg Mice

scholarly journals Allogeneic hematopoietic chimerism in mice treated with sublethal myeloablation and anti-CD154 antibody: absence of graft-versus-host disease, induction of skin allograft tolerance, and prevention of recurrent autoimmunity in islet-allografted NOD/Lt mice

Blood ◽  
2000 ◽  
Vol 95 (6) ◽  
pp. 2175-2182 ◽  
Author(s):  
Edward Seung ◽  
Neal Iwakoshi ◽  
Bruce A. Woda ◽  
Thomas G. Markees ◽  
John P. Mordes ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Mononuclear Cells ◽  
Autoimmune Diabetes ◽  
Third Party ◽  
Skin Allograft ◽  
Host Disease ◽  
Graft Versus Host ◽  
Islet Allografts ◽  
Hematopoietic Chimerism ◽  
Costimulatory Pathway

Abstract We describe a tolerance-based stem cell transplantation protocol that combines sublethal radiation with transient blockade of the CD40-CD154 costimulatory pathway using an anti-CD154 antibody. With this protocol, we established hematopoietic chimerism in BALB/c mice transplanted with fully allogeneic C57BL/6 bone marrow. The percentage of donor-origin mononuclear cells in recipients was more than 99%. In addition, all chimeric mice treated with anti-CD154 antibody remained free of graft-versus-host disease (GVHD) and accepted donor-origin but not third-party skin allografts. It was similarly possible to create allogeneic hematopoietic chimerism in NOD/Lt mice with spontaneous autoimmune diabetes. Pancreatic islet allografts transplanted into chimeric NOD/Lt mice were resistant not only to allorejection but also to recurrence of autoimmunity. We conclude that it is possible to establish robust allogeneic hematopoietic chimerism in sublethally irradiated mice without subsequent GVHD by blocking the CD40-CD154 costimulatory pathway using as few as 2 injections of anti-CD154 antibody. We also conclude that chimerism created in this way generates donor-specific allograft tolerance and reverses the predisposition to recurrent autoimmune diabetes in NOD/Lt mice, enabling them to accept curative islet allografts.

scholarly journals Transient antibody targeting of CD45RC inhibits the development of graft-versus-host disease

2020 ◽  
Vol 4 (11) ◽  
pp. 2501-2515 ◽  
Author(s):  
Laetitia Boucault ◽  
Maria-Dolores Lopez Robles ◽  
Allan Thiolat ◽  
Séverine Bézie ◽  
Michael Schmueck-Henneresse ◽  
...  
Keyword(s):  
T Cells ◽  
Graft Versus Host Disease ◽  
Rat Model ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Host Disease ◽  
Graft Versus Host ◽  
Nsg Mice ◽  
Donor Specific Tolerance ◽  
Specific Tolerance

Abstract Allogeneic bone marrow transplantation (BMT) is a widely spread treatment of many hematological diseases, but its most important side effect is graft-versus-host disease (GVHD). Despite the development of new therapies, acute GVHD (aGVHD) occurs in 30% to 50% of allogeneic BMT and is characterized by the generation of effector T (Teff) cells with production of inflammatory cytokines. We previously demonstrated that a short anti-CD45RC monoclonal antibody (mAb) treatment in a heart allograft rat model transiently decreased CD45RChigh Teff cells and increased regulatory T cell (Treg) number and function allowing long-term donor-specific tolerance. Here, we demonstrated in rat and mouse allogeneic GVHD, as well as in xenogeneic GVHD mediated by human T cells in NSG mice, that both ex vivo depletion of CD45RChigh T cells and in vivo treatment with short-course anti-CD45RC mAbs inhibited aGVHD. In the rat model, we demonstrated that long surviving animals treated with anti-CD45RC mAbs were fully engrafted with donor cells and developed a donor-specific tolerance. Finally, we validated the rejection of a human tumor in NSG mice infused with human cells and treated with anti-CD45RC mAbs. The anti-human CD45RC mAbs showed a favorable safety profile because it did not abolish human memory antiviral immune responses, nor trigger cytokine release in in vitro assays. Altogether, our results show the potential of a prophylactic treatment with anti-human CD45RC mAbs in combination with rapamycin as a new therapy to treat aGVHD without abolishing the antitumor effect.

scholarly journals Recombinant human interleukin-1 receptor antagonist in the treatment of steroid-resistant graft-versus-host disease

Blood ◽  
1994 ◽  
Vol 84 (4) ◽  
pp. 1342-1348 ◽  
Author(s):  
JH Antin ◽  
HJ Weinstein ◽  
EC Guinan ◽  
P McCarthy ◽  
BE Bierer ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Mononuclear Cells ◽  
Interleukin 1 ◽  
Response To Therapy ◽  
Mrna Levels ◽  
Steroid Resistant ◽  
Host Disease ◽  
Graft Versus Host

Abstract Acute graft-versus-host disease (GVHD) that is resistant to therapy is a highly lethal complication of marrow transplantation. Inflammatory cytokines such as interleukin-1 (IL-1) may be critical mediators of this process. If so, specific inhibition of IL-1 activity with recombinant human IL-1 receptor antagonist (IL-1Ra), a naturally occurring competitive inhibitor of IL-1, may ameliorate acute GVHD. We performed an open-label, phase I/II trial to evaluate the safety and efficacy of IL-1Ra in 17 patients with steroid-resistant GVHD. The IL- 1Ra was administered as a 24-hour continuous infusion over 7 days. The dose was escalated in cohorts of patients from 400 to 3,200 mg/d. Acute GVHD was evaluated in each affected organ and as an overall grade. Stage-specific improvement of acute GVHD occurred in the skin (8 of 14, 57%), gut (9 of 11, 82%), and liver (2 of 11, 18%). Overall, acute GVHD improved by at least one grade in 10 of 16 (63%) patients. Response to therapy was associated with a reduction of tumor necrosis factor-alpha (TNF-alpha) mRNA levels in blood mononuclear cells (P = .001). The only toxicity attributable to IL-1Ra was reversible transaminase elevation in two patients. Inhibition of IL-1 activity with IL-1Ra is safe and has demonstrable efficacy in acute GVHD that failed to respond to conventional treatment. These data provide further evidence that IL-1 is a mediator of GVHD.

Sign in / Sign up

Export Citation Format

Share Document