A New Murine Model Of Chronic Graft Versus Host Disease

Abstract Chronic graft-versus-host-disease (cGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), with highly variable clinical presentations. The pathophysiology of cGVHD remains to be further understood. The utilization of murine models to study cGVHD has contributed to the understanding of cGVHD, and highlights its mechanistic complexity. Here, we report a new murine cGVHD modle with obvious lung tissue damage in these mice resulted in the development of bronchiolitis obliterans (BO), which is pathopneumonic for cGVHD. Recipients 8 weeks BALB/c (H-2d) female mice, which irradiated with 700cGy dose of linear accelerator, then were injected with bone-marrow cells (1×107) and spleen cells (5×106) from (C57BL/6 x BALB/c) F1 donors (H-2bd haplotype) male mice. The observed items post-transplantation included hematopoietic reconstruction, implant, and general condition. Clinical scores were assessed every 3 days after +14 d. At + 135 d, mice were killed to evaluate the pathological changes of major target organs. Mice in transplantation groups were in hematopoietic reconstruction at +7 d, and all survived to the end point (+135 d). Chromosomes of recipient mice were in full donor chimera. Clinical scores of cGVHD group have been more than 0.6 since +90 d. These mice develop pathologic manifestations in several organs including lung, skin, and liver. Biopsy-proven BO incidence was 100%, and pathological scores of cGVHD group were 5.33±1.55, which significantly higher than those of transplantation control groups (P < 0.05). To date, most models involve parent-into-F1 combinations the transfer of MHC-mismatched cells resulted in a phenotype that resembles clinical systemic lupus erythematosus (SLE), termed SLE-cGVHD. However, some of the models do not use any pretransplantation conditioning and no obvious lung tissue damage. We exchanged parent for recipients, and provide a total boby irradiation as pretransplantation conditioning. New MHC-mismatched murine cGVHD model was easily obtained, and more relevancy to the clinical features of cGVHD. This model provides an ideal study model of clinical cGVHD pathogenesis and treatment strategies. NOTES: The project was sponsored by grants from National Natural Science Foundation (No. 81270648 and 30972790), National Public Health Grand Research Foundation (No.201202017), and Guangdong Natural Science Foundation (No. S2012010009560). Disclosures: No relevant conflicts of interest to declare.

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Complete Resolution of Extensive Chronic Graft-Versus-Host Disease with Ibrutinib

Blood ◽

10.1182/blood.v126.23.5474.5474 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5474-5474

Author(s):

Audrey Scholoff ◽

Gloria Obi ◽

Kelty R. Baker ◽

George Carrum ◽

Rammurti T Kamble

Keyword(s):

Graft Versus Host Disease ◽

Complete Resolution ◽

Conflicts Of Interest ◽

Complete Response ◽

Unrelated Donor ◽

Hematopoietic Stem ◽

Host Disease ◽

Graft Versus Host ◽

Oral Ulcers

Abstract We herein document a complete response of extensive chronic graft-versus-host disease (cGvHD) to a Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib. A 41 years old female with primary refractory MCL underwent mismatched unrelated donor (MMUD) allogeneic hematopoietic stem cell transplantation in December 2011 (conditioning with CY/TBI and alemtuzumab, graft=6.6x 106/kg CD-34+ cells, tacrolimus alone for GVHD prevention). Following engraftment on day 11, she developed grade III acute GvHD involving the skin and gut on day 17 of transplantation that persisted beyond 100 days post-transplant. Her cGvHD was treated with steroids, but remained active and extensive. Despite persistent cGvHD and 100% donor chimerism she relapsed in July 2012. Treatment with radiation and bendamustine with rituximab failed. By December 2013, the patient had extensive cGvHD manifesting as scleromatous skin thickening, oral ulcers and sclerosis of the buccal mucosa, ocular dryness and diarrhea, and was started on ibrutinib1 560 mg once daily for relapsed MCL. After 8 weeks of therapy, cGvHD had begun to improve. Oral steroids were reduced and ultimately stopped after 26 weeks of ibrutinib; after 30 weeks treatment all cGvHD manifestations resolved completely. A complete remission for MCL was documented at 8 weeks of ibrutinib initiation. Currently she continues to be on 560 mg daily ibrutinib without cGvHD exacerbation or MCL relapse for 22 weeks and 52 weeks, respectively. Chronic graft versus host disease (cGvHD) is mediated donor T cells. The role of B cells in the pathogenesis of cGvHD is increasingly recognized. Two murine studies have explored the role of ibrutinib in cGVHD-like syndromes, one in which there is T cell driven sclerodermatous cGvHD and a second in which there is Ab driven multiorgan system cGvHD that includes bronchiolitis obliterans (BO). Administration of ibrutinib decreased the incidence and severity of sclerodermatous, and improved pre-existing lesions and also improved pulmonary fibrosis and reduced BO. Animals lacking BTK and ITK did not develop cGVHD, indicating that these molecules are critical to cGVHD development. Our report provides the evidence that BTK inhibition led to complete resolution of cGvHD and supports exploration of its role in future clinical trials. Disclosures No relevant conflicts of interest to declare.

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Nanoparticle-Encapsulated Allogeneic T Cells Mitigate Graft-Versus-Host Disease but Retain Graft-Versus-Leukemia Activity

Blood ◽

10.1182/blood.v124.21.3820.3820 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3820-3820

Author(s):

Lingling Zhang ◽

Shuting Zhao ◽

Steven M. Devine ◽

Xiaoming He ◽

Jianhua Yu

Keyword(s):

T Cells ◽

Graft Versus Host Disease ◽

Conflicts Of Interest ◽

Hematopoietic Stem ◽

Host Disease ◽

Graft Versus Host ◽

Electrostatic Deposition ◽

Graft Versus Leukemia ◽

Donor T Cells

Abstract Allogeneic hematopoietic stem cell transplantation (HSCT) has curative potential for hematological malignancies, but is often associated with life-threatening complications including graft-versus-host disease (GVHD). The graft-versus-leukemia (GVL) activity which accompanies HSCT is responsible for eradication of tumor cells and prevention of relapse. GVHD and GVL are usually associated with each other and the separation of the two activities occurs in limited circumstances. In this study, we aimed to mitigate GVHD but retain GVL through transplantation of allogeneic T cells encapsulated with bio-degradable nanoparticle materials. For the above purpose, donor T cells were encapsulated with chitosan and alginate through layer-by-layer coating using electrostatic deposition. Encapsulated donor T cells were characterized in vitro, and their ability to inhibit GVHD and retain GVL was determined in vivo after being transplanted together with non-encapsulated donor bone marrow (BM) cells in a C57BL/6 → BALB/c HSCT mouse model. We found 85.7% of donor T cells were successfully encapsulated by the above method (Fig 1A). In vitro studies showed that the encapsulation did not change the phenotype of T cells as defined through the following parameters: size, viability, proliferation, antibody binding, cytokine secretion, and cytotoxicity of T cells (Fig. 1B and data not shown). Mice transplanted with encapsulated allogeneic T cells exhibited less severe acute GVHD and prolonged survival (Fig. 1 C-E). The mice showed a lower GVHD score, less liver damage, a smaller CD8/CD4 T cell ratio, and a higher number of donor BM-derived cells following transplantation with encapsulated donor T cells (Fig. 1 C-E and data not shown). When this GVHD model was combined with implantation of A20 lymphoma cells, GVL of encapsulated T cells was not compromised, while GVHD was still suppressed and the mouse survival also prolonged (Figure 2). In summary, nanoencapsulation of T cells with bio-degradable materials attenuated the severity of GVHD but retained GVL, presenting a novel and potentially safer and effective approach of allogeneic HSCT for future clinical application. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

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Effectiveness of Subcutaneous Low-Dose Alemtuzumab and Rituximab Combination Therapy for Steroid-Resistant Chronic Graft-Versus-Host Disease

Blood ◽

10.1182/blood.v118.21.4703.4703 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4703-4703

Author(s):

Cesar H Gutiérrez-Aguirre ◽

Juan A. Flores-Jiménez ◽

Olga Cantú-Rodríguez ◽

Jorge Cuervo-Sierra ◽

Adrián A. Ceballos-López ◽

...

Keyword(s):

Combination Therapy ◽

Graft Versus Host Disease ◽

Conflicts Of Interest ◽

Late Complication ◽

Low Doses ◽

Hematopoietic Stem ◽

Host Disease ◽

Graft Versus Host ◽

Steroid Refractory

Abstract Abstract 4703 Background: Chronic graft-versus-host disease (cGVHD) is a common late complication of allogeneic hematopoietic stem cell transplantation. Corticosteroids are the standard initial treatment for cGVHD. A second-line treatment is not well defined. We prospectively evaluated the effectiveness and safety of low doses of alemtuzumab and low doses of rituximab as treatment steroid-refractory cGVHD. Materials and Methods: Ten men and 5 women with cGVHD refractory to steroids and CSA were included. All patients received subcutaneous Alemtuzumab 10 mg/day/3 days and intravenous Rituximab 100 mg on days +1, +7, +14 and +21. Results: The median age was 41 years. The main organ involved were oral mucosa (86.7%), eyes (66.7%), liver (60%), skin (53%), lungs (13.3%) and intestinal tract (6.7%). The overall response was 100% at 30-day evaluation; 10 patients (67%) had partial remission (PR), and 5 patients (33%) had complete remission (CR). At 90-day evaluation, 7 (50%) patients had PR, 4 (28%) had CR; three (21%) relapsed and 1 patient not reached evaluation. Currently, 5 patients have reached the 365-day follow-up evaluation, 2 (40%) had PR, 2 had CR and 1 showed progression. The adverse effects were mainly infectious and one patient died from pneumonia. Conclusion: This combination therapy appears to be an efficacious and safe as treatment for steroid-refractory cGVHD. Disclosures: No relevant conflicts of interest to declare.

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LYG1 Deficiency Attenuates the Severity of Acute Graft-Versus-Host Disease Via Skewing T Cells Polarization Towards Treg Cells

Blood ◽

10.1182/blood-2020-141877 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 4-4

Author(s):

Huihui Liu ◽

Zhengyu Yu ◽

Bo Tang ◽

Shengchao Miao ◽

Chenchen Qin ◽

...

Keyword(s):

T Cells ◽

Graft Versus Host Disease ◽

Cd4 T Cells ◽

Bone Marrow Cells ◽

Conflicts Of Interest ◽

Treg Cells ◽

Hematopoietic Stem ◽

Host Disease ◽

Graft Versus Host ◽

Acute Graft

Acute graft-versus-host disease (aGVHD) is a lethal complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). As a complex immunopathology, aGVHD depends on the recognition of host antigens by donor T cells and induces augmented response of alloreactive T cells. Despite considerable achievements in the treatment of aGVHD, it remains a major clinical problem for the patients undergoing allo-HSCT. Therefore, it is necessary to further illustrate new mechanisms and develop novel therapeutic strategies of aGVHD. Previously we reported LYG1 (Lysozyme G-like 1) as a novel classical secretory protein promoted antitumor function of T cell. In this study, the role of LYG1 in aGVHD was investigated. Firstly, we examined whether LYG1 affected the alloreactivity of CD4+ T cells in vitro by MLR assay and discovered that LYG1 deficiency reduced the activation of CD4+ T cells and Th1 ratio, but increased Treg ratio. Then we confirmed these observations using a major MHC mismatched aGVHD model by transferring T cells sorting from WT B6 or Lyg1-/- mice with bone marrow cells from WT B6 mice into lethally irradiated BALB/c mice. The alloreactive CD4+ T cells and the proportions of Th1 cells decreased whereas the proportions of Treg cells increased in spleens and livers in mice receiving Lyg1-/- T cells. LYG1-deficient T cells attenuated aGVHD severity, inhibited the expression of CXCL9 and CXCL10 and restrained CD4+ T cells infiltrating in livers. Furthermore, administration of recombinant LYG1 protein intraperitoneally aggravated aGVHD by promoting IFN-γ production. More importantly, LYG1 deficiency did not affect GVT (graft-versus-tumor) effects. In summary, we demonstrate LYG1 regulates aGVHD via modulating the alloreactivity of CD4+ T cells and differentiation of Th1/Treg cells. Our study indicates that LYG1 may be a novel target in aGVHD by mitigating aGVHD without impairing GVT function. The therapeutic effect of targeting LYG1 is required in future investigations. Funding This study was supported by grant from The National Natural Science Foundation of China (NSFC) (Grant Number 81600144) and grant from Research Foundation of Peking University First Hospital. Disclosures No relevant conflicts of interest to declare.

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Regulatory T Cells Preserve Anti-Viral Immunity While Preventing Lethal Graft-Versus-Host Disease

Blood ◽

10.1182/blood.v122.21.5432.5432 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5432-5432

Author(s):

Thomas H. Winkler ◽

Martina Seefried ◽

Irena Kroeger ◽

Petra Hoffmann ◽

Matthias Edinger ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Graft Versus Host Disease ◽

Conflicts Of Interest ◽

Viral Immunity ◽

Post Transplantation ◽

Hematopoietic Stem ◽

Host Disease ◽

Graft Versus Host ◽

Cmv Reactivation

Abstract Graft-versus-host disease (GvHD) is a frequent and life-threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT) and is therefore one of the main factors that limits the broad application of HSCT. Over the last decades, several studies have reported a clinical association between GvHD and reactivation of cytomegalovirus (CMV). Using a lethal murine GvHD model with major MHC mismatch (C57BL/6 -> Balb/c), we were able to demonstrate that recipients latently infected with murine CMV (MCMV) before transplantation showed recurrence of CMV infection concomitant with the manifestation of GvHD. Moreover, these preinfected recipients showed an accelerated mortality compared to recipients that were not preinfected. The therapeutic co-infusion of CD4+CD25+ regulatory T cells (Tregs) with conventional T cells (Tcons) prevented lethal GvHD in preinfected mice and, markedly reduced the recurrence of MCMV infection. Remarkably, these mice showed clearance of MCMV 5 weeks post transplantation in contrast to mice receiving only Tcons in which massive virus infection persisted. Enhanced reconstitution of T lymphocytes and establishment of an anti-MCMV antibody titer from donor B cells in these animals suggest that CD4+CD25+ Tregs do not interfere with an anti-viral response while suppressing Tcon-mediated GvHD. Therefore, our study revealed that the suppressive function of CD4+CD25+ Tregs is not affected by CMV reactivation and more importantly, that Tregs do not adversely affect the anti-viral immunity in the recipient. In sum, these results provide important information on the correlation of GvHD and CMV reactivation and underline the possible clinical benefit of Treg application in GvHD patients. Disclosures: No relevant conflicts of interest to declare.

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A Selective TNFR2 Agonist Expands Host Treg Cells in Vivo to Protect from Acute Graft-Versus-Host Disease

Blood ◽

10.1182/blood.v124.21.1099.1099 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1099-1099 ◽

Cited By ~ 1

Author(s):

Andreas Beilhack ◽

Martin Chopra ◽

Marlene Biehl ◽

Martin Vaeth ◽

Andreas Brandl ◽

...

Keyword(s):

T Cells ◽

Graft Versus Host Disease ◽

Conflicts Of Interest ◽

Ex Vivo ◽

Hematopoietic Stem ◽

Peripheral Tissues ◽

Host Disease ◽

Graft Versus Host ◽

Pre Treatment

Abstract Donor CD4+Foxp3+ regulatory T cells (Tregs) suppress graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HCT) while maintaining the anti-tumoral effect of transplanted conventional T cells in preclinical mouse models. Current clinical study protocols with donor Tregs for treatment or prophylaxis of GVHD rely on their ex vivo expansion and infusion in high numbers. Here we present a fundamentally novel strategy for inhibiting GVHD that is based on the in vivo expansion of recipient Tregs prior to allo-HCT, exploiting the crucial role of tumor necrosis factor receptor 2 (TNFR2) in Treg biology. To this end we constructed a recombinant nonameric TNFR2-specific agonist, mimicking the activity of murine membrane-bound TNF on TNFR2 without TNFR1 stimulation, thereby avoiding the inflammatory side effects observed with conventional TNF. In vitro, this TNFR2-agonist expanded natural Tregs from wild type but not from TNFR2 KO mice. Accordingly, a human variant of this TNFR2-specific agonist expanded human Tregsin vitro. In vivo treatment of healthy mice with the murine TNFR2-agonist significantly increased Treg numbers in secondary lymphoid organs and peripheral tissues, particularly in the gastrointestinal tract, a prime target of acute GVHD. Next, we pre-treated recipient mice with this novel TNFR2-agonist to expand host-type radiation resistant Tregs prior to of allo-HCT in two models across MHC barriers (C57BL/6, H-2b->Balb/c, H-2d and FVB/N, H-2q->C57BL/6, H-2b). TNFR2-agonist pre-treatment resulted in significantly prolonged survival and reduced GVHD severity when compared to TNFR2-deficient recipients or untreated allo-HCT recipients. This was accompanied by reduced donor T cell proliferation and infiltration into GVHD target organs as assessed by in vivo and ex vivo bioluminescence imaging, flow cytometry and immunofluorescence microscopy. While in vivo TNFR2-agonist pre-treatment protected allo-HCT recipients from GVHD, anti-tumor effects of transplanted T cells remained unaffected in two different murine B cell leukemia models. In vivo depletion of host derived Tregs completely abrogated the protective effect of TNFR2-agonist pre-treatment. Our study shows that the expansion of host Tregs by selective in vivo TNFR2-activation significantly improves the outcome after allo-HCT and results in prolonged tumor-free survival. Disclosures No relevant conflicts of interest to declare.

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Ikaros Expression in the Graft Is Associated with Chronic Graft Versus Host Disease

Blood ◽

10.1182/blood-2020-138981 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 1-2

Author(s):

Andre Domingues Pereira ◽

Vinicius Campos de Molla ◽

Ana Rita Da Fonseca ◽

Yana Novis ◽

Marcela Souza Pires ◽

...

Keyword(s):

Graft Versus Host Disease ◽

Immune Reconstitution ◽

Opportunistic Infections ◽

Conflicts Of Interest ◽

Chronic Gvhd ◽

Hematopoietic Stem ◽

Host Disease ◽

Graft Versus Host ◽

Potential Biomarker ◽

Nih Classification

Introduction: Hematopoietic stem cell transplantation (HSCT) is the only potentially curative treatment for several diseases. Immune reconstitution post HSCT is a complex and extremely variable process. Ikaros transcription factor has an important role in hematopoiesis of several cell lines, especially in the lymphoid compartment. We hypothesized that Ikaros expression, both in the graft and in the recipient after transplant, might influence immune reconstitution and, consequently, the risk of opportunistic infections, relapse, and graft versus host disease (GVHD). Objectives: To correlate Ikaros expression both in the graft and in the recipient's peripheral blood (PB) after engraftment with the risk of GVHD after allogeneic HSCT outcomes. Patients and methods: 51 patients were included. Median age was 51 years (19-80), 53% of patients were male, and 57% of them had acute leukemia. Donor were haploidentical in 45% of cases, related identical in 29% and unrelated identical in 26%. Most patients (82%) received reduced-intensity conditioning regimens. Median follow-up was 20 months (10-40 months). Samples were collected from the graft and from the PB of the recipient 3 weeks after neutrophil recovery. Real time polymerase chain reaction (RT-PCR) was performed for analysis of absolute and relative Ikaros expression. Results: There was no association between Ikaros expression and the risk of acute GVHD, relapse or mortality. However, a significant association was observed in the risk of chronic GVHD. Cumulative incidence (CI) of chronic GVHD and of moderate / severe chronic GVHD (according to National Institute of Health - NIH classification) in two years were 49% and 28%, respectively. Higher Ikaros expression in the graft was associated with a significantly higher risk of moderate/severe chronic GVHD (54% vs. 15%, respectively, P=0.01). Higher Ikaros expression in the recipient's PB after engraftment was also associated with a significantly higher risk of moderate/severe chronic GVHD (65% vs. 11%, respectively, P=0.01). Conclusions: Ikaros expression in the graft and in the PB of the recipient after transplant seems to be correlated with a higher risk of moderate/severe chronic GVHD and might be evaluated in larger and prospective trials as a potential biomarker. Disclosures No relevant conflicts of interest to declare.

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Treatment of Severe Acute Graft-Versus-Host Disease with Mesenchymal Stromal Cells.

Blood ◽

10.1182/blood.v114.22.2249.2249 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2249-2249 ◽

Cited By ~ 2

Author(s):

Igor B Resnick ◽

Polina Stepensky ◽

Michael Y. Shapira ◽

Claudine Barkatz ◽

Gregory Elkin ◽

...

Keyword(s):

Mesenchymal Stromal Cells ◽

Graft Versus Host Disease ◽

Stromal Cells ◽

Acute Gvhd ◽

Cultured Cells ◽

Conflicts Of Interest ◽

Hematopoietic Stem ◽

Host Disease ◽

Graft Versus Host ◽

Gi Symptoms

Abstract Abstract 2249 Poster Board II-226 BACKGROUND. Allogeneic hematopoietic stem cell transplantation (HSCT) is being used to treat a range malignant and nonmalignant conditions. However, it often causes potentially lethal Graft-versus-Host Disease (GVHD). Several studies revealed that mesenchymal stromal cells (MSCs) from human bone marrow can down regulate GVHD after HSCT. METHODS. MSCs were obtained from BM, expanded and characterized by their morphology, immunophenotype, immunosuppressive potential for autologous, partially and fully mismatched lymphocytes. Twenty five patients (pts) got 39 (range, 1 to 4) MSCs infusions for 27 episodes of acute GVHD, which was defined as steroid resistant grade IV aGVHD in all but one patient. RESULTS. GvHD characteristics. Acute GVHD started from day +6 to d +46 from HSCT (median d+18) excluding single pt in whom it occurred on d+150. In 2 pts disease manifested in a hyper acute form before the engraftment (on d+6 and d+8, respectively). In all but one pt GI GVHD was defined as grade IV with full clinical picture of it. Skin GVHD accompanied GI symptoms in 17 pts and 13 was > grade II, in 4 grade IV. Liver symptoms presented in 13 pts, one pt was determinate as VOD. In 3 pts liver involvement was defined as grade IV. In all 24 of 25 pts had GVHD grade IV 4 and one grade III. Previous conventional anti GVHD therapies included: MP in all pts, MTX, various calcineurin inhibitors, MMF, ECP, serotherapy. Only 3 pts showed temporary limited partial response. Treatment with MSCs. The 1st infusion with MSC was given on day +32.5 (range, 8 to 74); d+50 (range, +28 to +180) post diagnosis of aGVHD and HSCT HSCT, respectively. In 22 evaluable pts we treated 24 separate episodes of GVHD: 22 first episodes and in 2 pts relapse of GVHD. In 24 of 39 cases treatment was performed with frozen MSC and in 15 with fresh cultured cells. In 37/39 cases passages 1 to 3 were used. Median number of infused cells was 1 (range, 0.3 to 3.1) x10 6 per kg of pt body weight in each treatment. Initial response was seen in 17/24 episodes of aGVHD (70.8%), in 8 partial (PR) and in 9 complete (CR). Two pts experienced GVHD relapse after achieving CR and very good PR: one case was treated successfully while another was resistant to MSCs. The latest pt with grade IV aggressive liver GVHD received MSCs injections intra hepatic arteries under radiological control following IRB approval with no anti GVHD effect. The procedure was uneventful with no evidence of microembolisation, no changes of blood flow or deterioration of liver tests (cytolysis). We observed a trend for better effect with higher MSC cell dose: total and per first infusion MSCs dose (1.93±1.28 vs. 1.23±0.50, p=0.078; 1.28±0.79 vs. 0.88±0.28, p=0.086). In all cases effect was seen after the first procedure. No difference was noted in the anti GVHD activity between fresh vs. frozen MSCs. There were no immediate or late toxicity or side effects. Overall survival. 14/25 patients are alive up to 20 months follow up. 8/11 pts, died from GVHD (4 within 1-10 d from MSCs infusion), and 3 from other unrelated causes including TTP-1, DAH-1 and disease progression-1. CONCLUSION. Treatment with MSCs seems to be a new novel type of therapy for steroids resistant GVHD with promising preliminary results and low toxicity. Obviously multicenter 2 arm randomized study is in need to confirm these encouraging. Disclosures: No relevant conflicts of interest to declare.

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Genetics of Intestinal Graft-Versus-Host Disease

Blood ◽

10.1182/blood.v118.21.sci-51.sci-51 ◽

2011 ◽

Vol 118 (21) ◽

pp. SCI-51-SCI-51

Author(s):

Marcel R.M. van den Brink

Keyword(s):

Graft Versus Host Disease ◽

Conflicts Of Interest ◽

Intestinal Flora ◽

Microbial Flora ◽

Intestinal Immunity ◽

Hematopoietic Stem ◽

Host Disease ◽

Graft Versus Host ◽

Intestinal Microbial Flora ◽

Intestinal Gvhd

Abstract SCI-51 Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an important therapy with curative potential for a variety of malignant and nonmalignant diseases. Despite standard prophylactic regimens, graft-versus-host disease (GVHD) continues to limit the success of outcomes in allo-HSCT patients. Gastrointestinal (GI) GVHD is the predominant contributor to acute GVHD-related mortality. The pathophysiology of GI GVHD has unique features that are related to the important interactions between the donor allograft (especially donor alloreactive T cells), mucosal adaptive and innate intestinal immunity, intestinal epithelial homeostasis, and the intestinal microbial flora. The pathophysiology of intestinal GVHD has many similarities with inflammatory bowel disease (IBD), such as Crohn’s disease and ulcerative colitis (UC). At last count, 99 susceptibility loci/genes for Crohn’s and UC have been published. Multiple genes are involved in IL-23/Th17 signaling, defective processing of intracellular bacteria involving autophagy and innate immunity (including NOD2 and ATG16L1), and defects in barrier function and shared susceptibility with other autoimmune diseases (such as type 1 and 2 DM). Early studies in mice and in patients suggested a link between an individual’s intestinal microbial flora and his/her propensity for GVHD resulting in varying protocols for gut decontamination, which continue at some centers to this date. We will discuss the latest data regarding the role in intestinal GVHD of genetic changes in the before-mentioned pathways and genes in the donor and host, as well as its interactions with the intestinal flora. Disclosures: No relevant conflicts of interest to declare.

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Resolution of Inflammation in Acute Graft-Versus-Host-Disease: Advances and Perspectives

Biomolecules ◽

10.3390/biom12010075 ◽

2022 ◽

Vol 12 (1) ◽

pp. 75

Author(s):

Layara Roberta Ferreira Duarte ◽

Vanessa Pinho ◽

Barbara Maximino Rezende ◽

Mauro Martins Teixeira

Keyword(s):

Graft Versus Host Disease ◽

Tissue Damage ◽

Inflammatory Responses ◽

Tissue Injury ◽

Inflammatory Diseases ◽

Resolution Of Inflammation ◽

Hematopoietic Stem ◽

Host Disease ◽

Graft Versus Host ◽

Potential Use

Inflammation is an essential reaction of the immune system to infections and sterile tissue injury. However, uncontrolled or unresolved inflammation can cause tissue damage and contribute to the pathogenesis of various inflammatory diseases. Resolution of inflammation is driven by endogenous molecules, known as pro-resolving mediators, that contribute to dampening inflammatory responses, promoting the resolution of inflammation and the recovery of tissue homeostasis. These mediators have been shown to be useful to decrease inflammatory responses and tissue damage in various models of inflammatory diseases. Graft-versus-host disease (GVHD) is a major unwanted reaction following allogeneic hematopoietic stem cell transplantation (allo-HSCT) and is characterized by an exacerbated inflammatory response provoked by antigen disparities between transplant recipient and donor. There is no fully effective treatment or prophylaxis for GVHD. This review explores the effects of several pro-resolving mediators and discusses their potential use as novel therapies in the context of GVHD.

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