Open AccessRole of interferon-γ in immune-mediated graft failure after allogeneic hematopoietic stem cell transplantation
Author(s) -
Pietro Merli,
Ignazio Caruana,
Rita De Vito,
Luisa Strocchio,
Gerrit Weber,
Francesca Del Bufalo,
Vanessa Buatois,
P. 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
Publication year - 2019
Publication title -
haematologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.782
H-Index - 142
eISSN - 1592-8721
pISSN - 0390-6078
DOI - 10.3324/haematol.2019.216101
Subject(s) - cxcl9 , immunology , cxcl10 , stem cell , hematopoietic stem cell transplantation , medicine , transplantation , chemokine , cd8 , hemophagocytic lymphohistiocytosis , t cell , bone marrow , haematopoiesis , monoclonal antibody , immune system , antibody , biology , disease , genetics
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.