C4d staining is a valuable marker in identifying chronic GVHD in colonic biopsies following BMT

Zhang, P L; Wilkerson, Myra L.; Schworer, Charles M.

doi:10.1038/bmt.2008.132

Cited by 6 publications

(4 citation statements)

References 4 publications

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“…4C, G demonstrate abundant C4d expression in immune cells that infiltrated skin lesions and show co-expression of Tax and C4d protein. Activated by the antigen-antibody reaction, C4d is an important marker in antibody-mediated humoral rejection after organ transplantation and also been reported to present after the occurrence of GVHD [45][46][47] . It might be a sign of interaction between viral infection and immune rejection during aGVHD progression 48 .…”

Section: Cells (Tablementioning

confidence: 99%

HTLV-1 infection of donor-derived T cells might promote acute graft-versus-host disease following liver transplantation

Shen

Wang

et al. 2022

Nat Commun

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Acute graft versus host disease (aGVHD) is a rare, but severe complication of liver transplantation (LT). It is caused by the activation of donor immune cells in the graft against the host shortly after transplantation, but the contributing pathogenic factors remain unclear. Here we show that human T cell lymphotropic virus type I (HTLV-1) infection of donor T cells is highly associated with aGVHD following LT. The presence of HTLV-1 in peripheral blood and tissue samples from a discovery cohort of 7 aGVHD patients and 17 control patients is assessed with hybridization probes (TargetSeq), mass cytometry (CyTOF), and multiplex immunohistology (IMC). All 7 of our aGVHD patients display detectable HTLV-1 Tax signals by IMC. We identify donor-derived cells based on a Y chromosome-specific genetic marker, EIF1AY. Thus, we confirm the presence of CD4+Tax+EIF1AY+ T cells and Tax+CD68+EIF1AY+ antigen-presenting cells, indicating HTLV-1 infection of donor immune cells. In an independent cohort of 400 patients, we verify that HTLV-1 prevalence correlates with aGVHD incidence, while none of the control viruses shows significant associations. Our findings thus provide new insights into the aetio-pathology of liver-transplantation-associated aGVHD and raise the possibility of preventing aGVHD prior to transplantation.

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Section: Cells (Tablementioning

confidence: 99%

HTLV-1 infection of donor-derived T cells might promote acute graft-versus-host disease following liver transplantation

Shen

Wang

et al. 2022

Nat Commun

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“…22,23 Some studies have suggested an implication of complement activation in human GVHD since C4d and C3 deposition has been observed in skin and gastrointestinal (GI) GVHD organs during acute and chronic GVHD. 7,24 Moreover, in vitro inhibition of C3 by compstatin has been reported to be able to reduce human CD4 and CD8 T cell proliferation and differentiation into Th1 and Th17 T cells. 7 The presented study was designed to prospectively explore the dynamic of complement activation early after allo-HSCT following a myeloablative conditioning (MAC) regimen.…”

Section: Introductionmentioning

confidence: 99%

“…Monitoring of circulating complement fractions C3, C4, and immune complexes reported increased levels in patients developing chronic GVHD 22,23 . Some studies have suggested an implication of complement activation in human GVHD since C4d and C3 deposition has been observed in skin and gastrointestinal (GI) GVHD organs during acute and chronic GVHD 7,24 . Moreover, in vitro inhibition of C3 by compstatin has been reported to be able to reduce human CD4 and CD8 T cell proliferation and differentiation into Th1 and Th17 T cells 7 …”

Section: Introductionmentioning

confidence: 99%

Systemic complement activation influences outcomes after allogeneic hematopoietic cell transplantation: A prospective French multicenter trial

et al. 2023

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Complement activation has shown a role in murine models of graft‐versus‐host disease (GVHD) and in endothelial complications after allogeneic hematopoietic cell transplantation (allo‐HSCT). However, its impact on post‐transplant outcomes has not been so far fully elucidated. Here, we conducted a prospective multicentric trial (NCT01520623) performing serial measurements of complement proteins, regulators, and CH50 activity for 12 weeks after allo‐HSCT in 85 patients receiving a myeloablative conditioning (MAC) regimen for various hematological malignancies. Twenty‐six out of 85 patients showed an “activated” complement profile through the classical/lectin pathway, defined as a post‐transplant decline of C3/C4 and CH50 activity. Time‐dependent Cox regression models demonstrated that complement activation within the first weeks after allo‐HSCT was associated with increased non‐relapse mortality (hazard ratio [HR]: 3.69, 95% confident interval [CI]: 1.55–8.78, p = .003) and poorer overall survival (HR: 2.72, 95% CI: 1.37–5.39, p = .004) due to increased incidence of grade II–IV acute GVHD and in particular gastrointestinal (GI) GVHD (HR: 36.8, 95% CI: 12.4–109.1, p < .001), higher incidences of thrombotic microangiopathy (HR: 8.58, 95% CI: 2.16–34.08, p = .0022), capillary leak syndrome (HR: 7.36, 95% CI: 2.51–21.66, p = .00028), post‐engraftment bacterial infections (HR: 2.37, 95% CI: 1.22–4.63, p = .0108), and EBV reactivation (HR: 3.33, 95% CI: 1.31–8.45, p = .0112). Through specific immune staining, we showed the correlation of deposition of C1q, C3d, C4d, and of C5b9 components on endothelial cells in GI GVHD lesions with the histological grade of GVHD. Altogether these findings define the epidemiology and the clinical impact of complement classical/lectin pathway activation after MAC regimens and provide a rational for the use of complement inhibitory therapeutics in a post‐allo‐HSCT setting.

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“…Furthermore, C3, C4 levels and circulating immune complexes were measured in 38 patients undergoing HLA-identical BMT and showed a strong association between the development of chronic GVHD and hypercomplementemia [15]. Recently, Zangh et al reported three cases of chronic GVHD identified in colon biopsies in which dilated capillaries were all positively stained for C4d, four months to two years following BMT [16].…”

Section: Introductionmentioning

confidence: 99%

The Role of Complement System in Graft versus Host Disease

Cherry¹,

Parekh²,

Lerner³

et al. 2015

J Blood Disord Transfus

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The role of complement system in stem cell transplantation is largely unknown. In solid organ transplantation, endovascular C4d deposition, a degradation product of the classic complement pathway, is essential for early rejection diagnosis. We retrospectively analyzed all patients diagnosed with graft versus host disease (GVHD) for C4d deposition at Oklahoma University between years 2000 and 2008. A modified Banff07 grading system was used to quantify C4d deposition. 58 biopsies (40 skin, 18 colon) performed on patients clinically suspected of having GVHD and 12 controls (all colon biopsies) were analyzed for C4d deposition. We recorded "response to steroids" in all clinical GVHD cases and looked at whether C4d can be utilized as a predictor of steroid treatment response. Of 40 clinical skin GVHD cases, 27 showed positive C4d staining which did not correlate well with steroid sensitivity: 74% of positive C4d cases responded to steroid therapy compared to 92% for negative cases (p=0.2634). 94% of colon GVHD cases showed positive C4d staining compared to 17% in controls (p<0.001). Only 44% of clinical colon GVHD cases were confirmed pathologically by H&E, compared to 93% of skin GVHD cases. For colon GVHD cases, 61% had clinical grade III/IV, and 78% responded to steroids. Interestingly, 90% of negative H&E colon cases responded to steroids. In conclusion, C4d deposition is a valuable marker for detection of colon GVHD, indicating a potential role of complement system in the pathogenesis of GVHD. C4d staining is potentially an objective tool than can help pathologist, in addition to H&E, to diagnosed colon GVHD.

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C4d staining is a valuable marker in identifying chronic GVHD in colonic biopsies following BMT

Cited by 6 publications

References 4 publications

HTLV-1 infection of donor-derived T cells might promote acute graft-versus-host disease following liver transplantation

HTLV-1 infection of donor-derived T cells might promote acute graft-versus-host disease following liver transplantation

Systemic complement activation influences outcomes after allogeneic hematopoietic cell transplantation: A prospective French multicenter trial

The Role of Complement System in Graft versus Host Disease

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