Role of interferon-γ in immune-mediated graft failure after allogeneic hematopoietic stem cell transplantation
Pietro Merli,
Ignazio Caruana,
Rita De Vito,
Luisa Strocchio,
Gerrit Weber,
Francesca Del Bufalo,
Vanessa Buatois,
Paolo Montanari,
Maria Giuseppina Cefalo,
Angela Pitisci,
Mattia Algeri,
Federica Galaverna,
Concetta Quintarelli,
Valentina Cirillo,
Daria Pagliara,
Walter Ferlin,
Maria Ballabio,
Cristina De Min,
Franco Locatelli
Affiliations
Pietro Merli
Bambino Ges Children’s Hospital, Department of Pediatric Hematology/Oncology, Cellular and Gene Therapy, Rome, Italy
Ignazio Caruana
Bambino Ges Children’s Hospital, Department of Pediatric Hematology/Oncology, Cellular and Gene Therapy, Rome, Italy
Rita De Vito
Bambino Gesù Children’s Hospital, Department of Laboratories, Pathology Unit, Rome, Italy
Luisa Strocchio
Bambino Ges Children’s Hospital, Department of Pediatric Hematology/Oncology, Cellular and Gene Therapy, Rome, Italy
Gerrit Weber
Bambino Ges Children’s Hospital, Department of Pediatric Hematology/Oncology, Cellular and Gene Therapy, Rome, Italy
Francesca Del Bufalo
Bambino Ges Children’s Hospital, Department of Pediatric Hematology/Oncology, Cellular and Gene Therapy, Rome, Italy
Vanessa Buatois
Novimmune SA, Geneva, Switzerland
Paolo Montanari
Novimmune SA, Geneva, Switzerland
Maria Giuseppina Cefalo
Bambino Ges Children’s Hospital, Department of Pediatric Hematology/Oncology, Cellular and Gene Therapy, Rome, Italy
Angela Pitisci
Bambino Ges Children’s Hospital, Department of Pediatric Hematology/Oncology, Cellular and Gene Therapy, Rome, Italy
Mattia Algeri
Bambino Ges Children’s Hospital, Department of Pediatric Hematology/Oncology, Cellular and Gene Therapy, Rome, Italy
Federica Galaverna
Bambino Ges Children’s Hospital, Department of Pediatric Hematology/Oncology, Cellular and Gene Therapy, Rome, Italy
Concetta Quintarelli
Bambino Ges Children’s Hospital, Department of Pediatric Hematology/Oncology, Cellular and Gene Therapy, Rome, Italy
Valentina Cirillo
Bambino Ges Children’s Hospital, Department of Pediatric Hematology/Oncology, Cellular and Gene Therapy, Rome, Italy
Daria Pagliara
Bambino Ges Children’s Hospital, Department of Pediatric Hematology/Oncology, Cellular and Gene Therapy, Rome, Italy
Walter Ferlin
Novimmune SA, Geneva, Switzerland
Maria Ballabio
Novimmune SA, Geneva, Switzerland
Cristina De Min
Novimmune SA, Geneva, Switzerland
Franco Locatelli
Bambino Ges Children’s Hospital, Department of Pediatric Hematology/Oncology, Cellular and Gene Therapy, Rome, Italy;Department of Pediatrics, Sapienza, University of Rome, Rome, Italy
Pathophysiology of graft failure (GF) occurring after allogeneic hematopoietic stem cell transplantation (HSCT) still remains elusive. We measured serum levels of several different cytokines/chemokines in 15 children experiencing GF, comparing their values with those of 15 controls who had sustained donor cell engraftment. Already at day +3 after transplantation, patients developing GF had serum levels of interferon (IFN)-γ and CXCL9 (a chemokine specifically induced by IFNγ) significantly higher than those of controls (8859±7502 vs. 0 pg/mL, P=0.03, and 1514.0±773 vs. 233.6±50.1 pg/mlL, P=0.0006, respectively). The role played by IFNγ in HSCT-related GF was further supported by the observation that a rat anti-mouse IFNγ-neutralizing monoclonal antibody promotes donor cell engraftment in Ifngr1−/−mice receiving an allograft. In comparison to controls, analysis of bone marrow-infiltrating T lymphocytes in patients experiencing GF documented a predominance of effector memory CD8+ cells, which showed markers of activation (overexpression of CD95 and downregulation of CD127) and exhaustion (CD57, CD279, CD223 and CD366). Finally, we obtained successful donor engraftment in 2 out of 3 children with primary hemophagocytic lymphohistiocytosis who, after experiencing GF, were re-transplanted from the same HLA-haploidentical donor under the compassionate use coverage of emapalumab, an anti-IFNγ monoclonal antibody recently approved by the US Food and Drug Administration for treatment of patients with primary hemophagocytic lymphohistiocytosis. Altogether, these results suggest that the IFNγ pathway plays a major role in GF occurring after HSCT. Increased serum levels of IFNγ and CXCL9 represent potential biomarkers useful for early diagnosis of GF and provide the rationale for exploring the therapeutic/preventive role of targeted neutralization of IFNγ.
