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

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.

[1]  K. Markey,et al.  The contribution of the intestinal microbiome to immune recovery after HCT , 2022, Frontiers in Immunology.

[2]  J. Atkinson,et al.  C5b-9 and MASP2 deposition in skin and bone marrow microvasculature characterize hematopoietic stem cell transplant-associated thrombotic microangiopathy , 2022, Bone Marrow Transplantation.

[3]  A. Fodor,et al.  Microbiota dynamics in a randomized trial of gut decontamination during allogeneic hematopoietic cell transplantation , 2022, JCI insight.

[4]  Nicholas R. Waters,et al.  Early intestinal microbial features are associated with CD4 T cell recovery after allogeneic hematopoietic transplant. , 2022, Blood.

[5]  T. Fujita,et al.  Role of the lectin pathway of complement in hematopoietic stem cell transplantation-associated endothelial injury and thrombotic microangiopathy , 2021, Experimental Hematology & Oncology.

[6]  P. Validire,et al.  Complement C1s and C4d as Prognostic Biomarkers in Renal Cancer: Emergence of Noncanonical Functions of C1s , 2021, Cancer Immunology Research.

[7]  Youssif M. Ali,et al.  Inhibition of the Classical Pathway of Complement Activation Impairs Bacterial Clearance during Enterococcus faecalis Infection , 2021, Infection and Immunity.

[8]  P. Zipfel,et al.  How Does Complement Affect Hematological Malignancies: From Basic Mechanisms to Clinical Application , 2020, Frontiers in Immunology.

[9]  M. Medvedovic,et al.  Interferon-complement loop in transplant-associated thrombotic microangiopathy. , 2020, Blood advances.

[10]  A. Alawieh,et al.  Targeting the Complement Alternative Pathway Permits Graft Versus Leukemia Activity while Preventing Graft Versus Host Disease , 2020, Clinical Cancer Research.

[11]  R. Zeiser.  Advances in understanding the pathogenesis of graft‐versus‐host disease , 2019, British journal of haematology.

[12]  M. Robin,et al.  Allogeneic reactivity-mediated endothelial cell complications after HSCT: a plea for consensual definitions. , 2019, Blood advances.

[13]  D. Fairlie,et al.  Complement C3a and C5a receptors promote GVHD by suppressing mitophagy in recipient dendritic cells. , 2018, JCI insight.

[14]  S. Davies,et al.  Circulating dsDNA, endothelial injury, and complement activation in thrombotic microangiopathy and GVHD. , 2017, Blood.

[15]  J. Magenau,et al.  Advances in understanding the pathogenesis of graft‐versus‐host disease , 2016, British journal of haematology.

[16]  Lubka T. Roumenina,et al.  Complement System Part II: Role in Immunity , 2015, Front. Immunol..

[17]  B. Dixon,et al.  A new paradigm: Diagnosis and management of HSCT-associated thrombotic microangiopathy as multi-system endothelial injury. , 2015, Blood reviews.

[18]  H. Greinix,et al.  National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease , 2015 .

[19]  F. Zou,et al.  The genetic fingerprint of susceptibility for transplant-associated thrombotic microangiopathy. , 2015, Blood.

[20]  K. Tsai,et al.  Complement component C3 mediates Th1/Th17 polarization in human T-cell activation and cutaneous GVHD , 2014, Bone Marrow Transplantation.

[21]  P. Cravedi,et al.  Complement regulation of T-cell alloimmunity. , 2013, Seminars in nephrology.

[22]  G. Socié,et al.  Successful use of eculizumab in a patient with post‐transplant thrombotic microangiopathy , 2013, British journal of haematology.

[23]  R. Nurieva,et al.  Reduced graft-versus-host disease in C3-deficient mice is associated with decreased donor Th1/Th17 differentiation. , 2012, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[24]  M. Merad,et al.  Antigen-presenting cell-derived complement modulates graft-versus-host disease. , 2012, The Journal of clinical investigation.

[25]  G. Lombardi,et al.  Functional modulation of human monocytes derived DCs by anaphylatoxins C3a and C5a , 2012, Immunobiology.

[26]  S. Steinberg,et al.  Sclerotic-type chronic GVHD of the skin: clinical risk factors, laboratory markers, and burden of disease. , 2011, Blood.

[27]  M. Lerner,et al.  The Role of Complement System in the Pathogenesis of Graft Versus Host Disease , 2011 .

[28]  T. Woodruff,et al.  Dendritic Cell Function in Allostimulation Is Modulated by C5aR Signaling1 , 2009, The Journal of Immunology.

[29]  K. Washington,et al.  Pathology of graft-versus-host disease in the gastrointestinal tract. , 2009, Human pathology.

[30]  P. Heeger,et al.  Locally produced C5a binds to T cell-expressed C5aR to enhance effector T-cell expansion by limiting antigen-induced apoptosis. , 2008, Blood.

[31]  C. Schworer,et al.  C4d staining is a valuable marker in identifying chronic GVHD in colonic biopsies following BMT , 2008, Bone Marrow Transplantation.

[32]  R. Smith,et al.  Local production and activation of complement up-regulates the allostimulatory function of dendritic cells through C3a-C3aR interaction. , 2008, Blood.

[33]  A. Caudy,et al.  Genetic and functional analyses of membrane cofactor protein (CD46) mutations in atypical hemolytic uremic syndrome. , 2006, Journal of the American Society of Nephrology : JASN.

[34]  Daniel Wolff,et al.  National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report. , 2005, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[35]  H. Rus,et al.  Both apoptosis and complement membrane attack complex deposition are major features of murine acute graft-vs.-host disease. , 2005, Experimental and molecular pathology.

[36]  A. Valujskikh,et al.  Decay-accelerating factor modulates induction of T cell immunity , 2005, The Journal of experimental medicine.

[37]  J. Lambris,et al.  The complement inhibitory protein DAF (CD55) suppresses T cell immunity in vivo , 2005, The Journal of experimental medicine.

[38]  W. Fridman,et al.  Complement factor I: a susceptibility gene for atypical haemolytic uraemic syndrome , 2004, Journal of Medical Genetics.

[39]  G. Deschênes,et al.  Heterozygous and homozygous factor h deficiencies associated with hemolytic uremic syndrome or membranoproliferative glomerulonephritis: report and genetic analysis of 16 cases. , 2004, Journal of the American Society of Nephrology : JASN.

[40]  N. Breslau,et al.  Graphing survival curve estimates for time‐dependent covariates , 2002, International journal of methods in psychiatric research.

[41]  T. Spitzer.  Engraftment syndrome following hematopoietic stem cell transplantation , 2001, Bone Marrow Transplantation.

[42]  P. Grambsch,et al.  Modeling Survival Data: Extending the Cox Model , 2000 .

[43]  Robert Gray,et al.  A Proportional Hazards Model for the Subdistribution of a Competing Risk , 1999 .

[44]  E D Thomas,et al.  1994 Consensus Conference on Acute GVHD Grading. , 1995, Bone marrow transplantation.

[45]  G. Füst,et al.  Clinical significance of longitudinal complement measurements in recipients of bone marrow transplant. , 1995, Bone marrow transplantation.

[46]  H. Shulman,et al.  Hepatic veno-occlusive disease--liver toxicity syndrome after bone marrow transplantation. , 1992, Bone marrow transplantation.

[47]  Paula Vieira Martins,et al.  Sheep Erythrocyte Preparation for Hemolytic Tests Exploring Complement Functional Activities. , 2021, Methods in molecular biology.

[48]  J. Bay,et al.  [Intestinal microbiota and allogeneic stem cell transplantation]. , 2019 .

[49]  J. Moake,et al.  Diagnostic criteria for hematopoietic stem cell transplant-associated microangiopathy: results of a consensus process by an International Working Group. , 2007, Haematologica.

[50]  J. Atkinson,et al.  T-cell regulation: with complements from innate immunity , 2007, Nature Reviews Immunology.

[51]  R Simon,et al.  A non-parametric graphical representation of the relationship between survival and the occurrence of an event: application to responder versus non-responder bias. , 1984, Statistics in medicine.