Reduced Expression of VAMP8 in Lacrimal Gland Affected by Chronic Graft-versus-Host Disease

Purpose. To investigate whether the SNARE protein vesicle-associated membrane protein 8 (VAMP8) was implicated in the development of chronic ocular graft-versus-host disease (GVHD). Methods. Firstly, the chronic GVHD (cGVHD) and Sjögren’s syndrome (SS)-impaired lacrimal gland (LG) tissue sections from humans for diagnostic purpose were evaluated for VAMP8 expression by histopathology and immunohistochemistry. Next, serial changes of tear secretion and VAMP8 expression at both protein and mRNA level of LG in an animal cGVHD model compared with the syngeneic control. Results. Decreased VAMP 8 expression in the cGVHD-affected human LG was detected in comparison with SS-affected LG. Tear secretion in the murine cGVHD model was significantly reduced compared with that in the syngeneic controls 8 weeks after BMT. Protein expression of VAMP8 in the cGVHD-affected LG in murine cGVHD was decreased in comparison with that in the controls. Gene expression of VAMP8 in the cGVHD-affected murine LG was significantly less than that in the syngeneic control 3 weeks after BMT. Conclusions. Our results suggested that expression of VAMP8 in the cGVHD-affected LG was decreased and accordingly tear secretion in cGVHD was reduced. Collectively, the reduction of VAMP8 expression in the cGVHD-affected LG can be involved in the pathogenic processes of cGVHD-induced dry eye disease.

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Mast Cell Involvement in Fibrosis in Chronic Graft-Versus-Host Disease

International Journal of Molecular Sciences ◽

10.3390/ijms22052385 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2385

Author(s):

Ethan Strattan ◽

Gerhard Carl Hildebrandt

Keyword(s):

Wound Healing ◽

Mast Cell ◽

Mast Cells ◽

Graft Versus Host Disease ◽

Chronic Gvhd ◽

Fibrotic Disease ◽

Acute Leukemias ◽

Hematopoietic Stem ◽

Host Disease ◽

Graft Versus Host

Allogeneic hematopoietic stem cell transplantation (HSCT) is most commonly a treatment for inborn defects of hematopoiesis or acute leukemias. Widespread use of HSCT, a potentially curative therapy, is hampered by onset of graft-versus-host disease (GVHD), classified as either acute or chronic GVHD. While the pathology of acute GVHD is better understood, factors driving GVHD at the cellular and molecular level are less clear. Mast cells are an arm of the immune system that are known for atopic disease. However, studies have demonstrated that they can play important roles in tissue homeostasis and wound healing, and mast cell dysregulation can lead to fibrotic disease. Interestingly, in chronic GVHD, aberrant wound healing mechanisms lead to pathological fibrosis, but the cellular etiology driving this is not well-understood, although some studies have implicated mast cells. Given this novel role, we here review the literature for studies of mast cell involvement in the context of chronic GVHD. While there are few publications on this topic, the papers excellently characterized a niche for mast cells in chronic GVHD. These findings may be extended to other fibrosing diseases in order to better target mast cells or their mediators for treatment of fibrotic disease.

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Non-Relapse Mortality Among Patients Diagnosed with Chronic Graft-Versus-Host Disease: An Updated Analysis from the Chronic Gvhd Consortium

Transplantation and Cellular Therapy ◽

10.1016/s2666-6367(21)00109-3 ◽

2021 ◽

Vol 27 (3) ◽

pp. S79-S80

Author(s):

Zachariah DeFilipp ◽

Lynn Onstad ◽

Sally Arai ◽

Mukta Arora ◽

Corey Cutler ◽

...

Keyword(s):

Graft Versus Host Disease ◽

Chronic Gvhd ◽

Host Disease ◽

Graft Versus Host

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Immune Mediated Cerebellar Ataxia: An Unknown Manifestation of Graft-versus-Host Disease

Acta Haematologica ◽

10.1159/000494423 ◽

2018 ◽

Vol 141 (1) ◽

pp. 19-22

Author(s):

Liat Shargian-Alon ◽

Pia Raanani ◽

Uri Rozovski ◽

Tali Siegal ◽

Shlomit Yust-Katz ◽

...

Keyword(s):

Cerebellar Ataxia ◽

Graft Versus Host Disease ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Cerebellar Atrophy ◽

Acid Decarboxylase ◽

High Dose ◽

Host Disease ◽

Graft Versus Host ◽

Aged Woman

Neurologic complications of allogeneic hematopoietic cell transplantation (allo-HCT) include infections, cerebrovascular events, therapy-induced neurotoxicity, recurrent malignancies, and neurologic manifestations of graft-versus-host disease (GVHD). Anti-glutamic acid decarboxylase (GAD) antibody-associated cerebellar ataxia is a well-established disorder of autoimmune origin, but there are no reports in the literature of its occurrence following allo-HCT. We describe a middle-aged woman with chronic GVHD after allo-HCT who presented with a rapidly progressive cerebellar syndrome. Thorough investigation revealed only cerebellar atrophy on brain imaging and positive anti-GAD65 antibodies in serum and cerebrospinal fluid suggesting the diagnosis of anti-GAD antibody-associated cerebellar ataxia. Despite prompt treatment with high-dose corticosteroids, intravenous immunoglobulins, and rituximab, the patient’s condition rapidly deteriorated, and she died 4 months later. This case suggests that anti-GAD antibody-associated cerebellar ataxia may be a rare manifestation of chronic GVHD.

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Acute and chronic graft versus host disease after hematopoietic stem cell transplant

JBMTCT ◽

10.46765/2675-374x.2020v1n1p53-66 ◽

2020 ◽

Vol 1 (1) ◽

pp. 53-66

Author(s):

Vaneuza A. M. Funke ◽

Maria Claudia Rodrigues Moreira ◽

Afonso Celso Vigorito

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell ◽

Graft Versus Host Disease ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Cell Transplant ◽

Primary Therapy ◽

Hematopoietic Stem ◽

Host Disease ◽

Graft Versus Host

Graft versus host disease is one of the main complications of Hematopoietic stem cell, involving about 50% to 80% of the patients. Acute GVHD clinical manifestations and therapy is discussed, as well as new NIH criteria for the diagnosis and classification of chronic GVHD. Therapy for both refractory chronic and acute GVHD is an important field of discussion once there is no superiority for the majority of the agents after primary therapy has failed. Hence, this review is meant to be a useful tool of consultation for clinicians who are dealing with this complex complication.

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Bone marrow transplantation for severe aplastic anemia: influence of conditioning and graft-versus-host disease prophylaxis regimens on outcome

Blood ◽

10.1182/blood.v79.1.269.bloodjournal791269 ◽

1992 ◽

Vol 79 (1) ◽

pp. 269-275 ◽

Cited By ~ 2

Author(s):

E Gluckman ◽

MM Horowitz ◽

RE Champlin ◽

JM Hows ◽

A Bacigalupo ◽

...

Keyword(s):

Bone Marrow ◽

Aplastic Anemia ◽

Graft Versus Host Disease ◽

Randomized Clinical Trials ◽

Chronic Gvhd ◽

Severe Aplastic Anemia ◽

Term Survival ◽

Host Disease ◽

Graft Versus Host ◽

Gvhd Prophylaxis

Data for 595 patients with severe aplastic anemia receiving HLA- identical sibling bone marrow transplants were analyzed to determine the effect of pretransplant conditioning and graft-versus-host disease (GVHD) prophylaxis on outcome. Transplants were performed between 1980 and 1987 and reported to the International Bone Marrow Transplant Registry. Three conditioning regimens (cyclophosphamide alone, cyclophosphamide plus limited field radiation, and cyclophosphamide plus total body radiation) were studied; none was associated with superior long-term survival. Three GVHD prophylaxis regimens (methotrexate, cyclosporine, and methotrexate plus cyclosporine) were studied. Recipients of cyclosporine with or without methotrexate had a significantly higher probability of 5-year survival (69%, 95% confidence interval 63% to 74%) than patients receiving methotrexate only (56%, 49% to 62%, P less than .003). Higher survival with cyclosporine resulted from decreased risks of interstitial pneumonia (P less than .0002) and chronic GVHD (P less than .005). Additional risk factors adversely associated with survival included infection pretransplant (P less than .004), use of parous or transfused female donors (P less than .005), older patient age (P less than .005), and 20 or more pretransplant transfusions (P less than .006). These data may prove useful in planning randomized clinical trials and in identifying patients at high-risk of treatment failure.

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Ruxolutinib in Steroid Refractory Graft Versus Host Disease (SR-GVHD): Systemic Literature Review

Blood ◽

10.1182/blood-2019-129538 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5682-5682

Author(s):

Mostafa F. Mohammed Saleh ◽

Shahrukh K. Hashmi

Keyword(s):

Adverse Events ◽

Graft Versus Host Disease ◽

Chronic Gvhd ◽

Infectious Complications ◽

Systemic Review ◽

Close Monitoring ◽

Hematopoietic Stem ◽

Host Disease ◽

Graft Versus Host ◽

Steroid Refractory

Background: Graft versus host disease (GVHD) is a main cause of morbidity and mortality in patients having undergone allogeneic hematopoietic stem cell transplantation (HSCT). About 30-40% of patients have steroid‐refractory GVHD (SR‐GVHD) after the first‐line use of high doses of corticosteroids with a poor prognosis .Ruxolitinib is a promising treatment for SR-GVHD. However, data regarding optimum dosing, response rates and associated adverse events are scarce. Herein, we provide the first systemic review of literature for the use ruxolutinib in GVHD. Methods: A Medline (PubMed), google scholar, OVID and Cochrane Database of Systematic Reviews search using key words "Ruxolutinib and GVHD", "Ruxolutinib and SR-GVHD" was undertaken in June 2019. Only peer reviewed databases were searched and search was restricted to human studies of acute and chronic GVHD only. Results: 16 publications, as listed in Table 1. Only one was a prospective trial, all others were retrospective studies, case series (5), and case reports (2). Overall response, ranged 45% - 100%, complete response was noted in 5.2% -80% patients. Time to response was variable from 1-12 weeks. Cytopenias and infectious complications were frequently reported with dose reduction or interruptions needed in most studies. Maintained responses were reported in a small proportion after ruxolutinib discontinuation. Conclusion Ruxolutinib has promising efficacy in SR-GVHD , however cytopenias and infectious complications reported frequently mandate close monitoring. Results of ongoing prospective trials could provide answers for optimum dosing and response assessment, and management of related adverse events. Table Disclosures No relevant conflicts of interest to declare.

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The role of antigen-presenting cells in triggering graft-versus-host disease and graft-versus-leukemia

Blood ◽

10.1182/blood-2006-12-022038 ◽

2007 ◽

Vol 110 (1) ◽

pp. 9-17 ◽

Cited By ~ 108

Author(s):

Ronjon Chakraverty ◽

Megan Sykes

Keyword(s):

Graft Versus Host Disease ◽

Acute Gvhd ◽

Tissue Injury ◽

Chronic Gvhd ◽

Host Disease ◽

Graft Versus Host ◽

Graft Versus Leukemia ◽

Donor T Cells ◽

Antigen Presenting

After allogeneic blood or bone marrow transplantation, donor T cells interact with a distorted antigen-presenting cell (APC) environment in which some, but not all, host APCs are replaced by APCs from the donor. Significantly, host APCs are required for the priming of acute graft-versus-host disease (GVHD). Donor APCs play a lesser role in the induction of acute GVHD despite their predicted capacity to cross-present host antigens. In contrast, donor APCs may play a role in perpetuating the tissue injury observed in chronic GVHD. Host APCs are also required for maximal graft-versus-leukemia responses. Recent studies have suggested potential strategies by which the continued presence of host APCs can be exploited to prime strong donor immunity to tumors without the induction of GVHD.

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Chronic graft versus host disease is associated with long-term risk for pneumococcal infections in recipients of bone marrow transplants

Blood ◽

10.1182/blood.v95.12.3683 ◽

2000 ◽

Vol 95 (12) ◽

pp. 3683-3686 ◽

Cited By ~ 99

Author(s):

Samar Kulkarni ◽

Ray Powles ◽

Jennie Treleaven ◽

Unell Riley ◽

Seema Singhal ◽

...

Keyword(s):

Graft Versus Host Disease ◽

Chronic Gvhd ◽

Pneumococcal Infection ◽

Pneumococcal Infections ◽

Hematopoietic Stem ◽

Host Disease ◽

Graft Versus Host ◽

Increased Risk ◽

Penicillin Prophylaxis

Abstract Incidences of and risk factors for Streptococcus pneumoniaesepsis (SPS) after hematopoietic stem cell transplantation were analyzed in 1329 patients treated at a single center between 1973 and 1997. SPS developed in 31 patients a median of 10 months after transplantation (range, 3 to 187 months). The infection was fatal in 7 patients. The probability of SPS developing at 5 and 10 years was 4% and 6%, respectively. Age, sex, diagnosis, and graft versus host disease (GVHD) prophylaxis did not influence the development of SPS. Allogeneic transplantation (10-year probability, 7% vs 3% for nonallogeneic transplants; P = .03) and chronic GVHD (10-year probability, 14% vs 4%; P = .002) were associated with significantly higher risk for SPS. All the episodes of SPS were seen in patients who had undergone allograft or total body irradiation (TBI) (31 of 1202 vs 0 of 127;P = .07). Eight patients were taking regular penicillin prophylaxis at the time of SPS, whereas 23 were not taking any prophylaxis. None of the 7 patients with fatal infections was taking prophylaxis for Pneumococcus. Pneumococcal bacteremia was associated with higher incidences of mortality (6 of 15 vs 1 of 16;P = .04). We conclude that there is a significant long-term risk for pneumococcal infection in patients who have undergone allograft transplantation, especially those with chronic GVHD. Patients who have undergone autograft transplantation after TBI-containing regimens also appear to be at increased risk. These patients should receive lifelong pneumococcus prophylaxis. Consistent with increasing resistance to penicillin, penicillin prophylaxis does not universally prevent SPS, though it may protect against fatal infections. Further studies are required to determine the optimum prophylactic strategy in patients at risk.

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Ixazomib for Treatment of Refractory Chronic Graft-versus-Host Disease: A Chronic GVHD Consortium Phase II Trial

Biology of Blood and Marrow Transplantation ◽

10.1016/j.bbmt.2020.05.015 ◽

2020 ◽

Vol 26 (9) ◽

pp. 1612-1619

Author(s):

Joseph Pidala ◽

Vijaya R. Bhatt ◽

Betty Hamilton ◽

Iskra Pusic ◽

William A. Wood ◽

...

Keyword(s):

Phase Ii ◽

Graft Versus Host Disease ◽

Phase Ii Trial ◽

Chronic Gvhd ◽

Host Disease ◽

Graft Versus Host

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Influence of acute and chronic graft-versus-host disease on relapse and survival after bone marrow transplantation from HLA-identical siblings as treatment of acute and chronic leukemia [published erratum appears in Blood 1989 Aug 15;74(3):1180]

Blood ◽

10.1182/blood.v73.6.1720.1720 ◽

1989 ◽

Vol 73 (6) ◽

pp. 1720-1728 ◽

Cited By ~ 430

Author(s):

KM Sullivan ◽

PL Weiden ◽

R Storb ◽

RP Witherspoon ◽

A Fefer ◽

...

Keyword(s):

Graft Versus Host Disease ◽

Marrow Transplantation ◽

Acute Gvhd ◽

Blast Crisis ◽

Chronic Gvhd ◽

Chronic Phase ◽

Lymphocytic Leukemia ◽

Myelogenous Leukemia ◽

Host Disease ◽

Graft Versus Host

Abstract To assess the influence of graft-versus-host disease (GVHD) on recurrent leukemia and survival after allogeneic marrow transplantation, we studied 1,202 patients with acute nonlymphocytic leukemia (ANL), acute lymphocytic leukemia (ALL), and chronic myelogenous leukemia (CML) given unmodified marrow grafts from HLA- identical siblings. Proportional hazards regression models using acute GVHD and chronic GVHD as time-dependent covariates demonstrated a significant association of GVHD with a decreased relative risk (RR, 0.33 to 0.42) of relapse in patients with ANL, ALL, and CML transplanted in advanced disease. Among patients developing either acute or chronic GVHD, treatment failure (that is, mortality or relapse) was decreased in patients with ALL transplanted in relapse (RR = 0.70, P less than .033) and CML in blast crisis (RR = 0.37, P less than .009). This effect was independent of age, sex, preparative regimen, GVHD prophylaxis, or length of follow-up. Five-year actuarial estimates were derived for the subset of 657 patients who survived in remission 150 days after transplant and were at risk for development of chronic GVHD. Among patients with ANL in first remission or CML in chronic phase, GVHD had an adverse effect on survival and no apparent influence on relapse. Among patients with ANL and ALL transplanted in relapse, the probability of relapse after day 150 was 74% without [corrected] GVHD, 45% with acute and chronic GVHD, 35% with [corrected] only acute GVHD, and 34% with only chronic GVHD (P less than .001). Actuarial survival in these four GVHD groups was 25%, 34%, 59%, and 62%, respectively (P less than .009). Among patients with CML in acceleration or blast crisis, the probability of relapse after day 150 was 65% without GVHD and 36% with acute and/or chronic GVHD (P less than .017). We conclude that acute and chronic GVHD were associated with a durable antileukemic effect and improved survival in patients transplanted in advanced stages of ALL and CML.

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