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Ferrata Storti Foundation
Haematologica 2019 Volume 104(11):2314-2323
Stem Cell Transplantation
Role of interferon-γ in immune-mediated graft failure after allogeneic hematopoietic stem cell transplantation
Pietro Merli,1 Ignazio Caruana,1 Rita De Vito,2 Luisa Strocchio,1 Gerrit Weber,1 Francesca Del Bufalo,1 Vanessa Buatois,3 Paolo Montanari,3 Maria Giuseppina Cefalo,1 Angela Pitisci,1 Mattia Algeri,1 Federica Galaverna,1 Concetta Quintarelli,1 Valentina Cirillo,1 Daria Pagliara,1 Walter Ferlin,3 Maria Ballabio,3 Cristina De Min3 and Franco Locatelli1,4
1Bambino Gesù Children’s Hospital, Department of Pediatric Hematology/Oncology, Cellular and Gene Therapy, Rome, Italy; 2Bambino Gesù Children’s Hospital, Department of Laboratories, Pathology Unit, Rome, Italy; 3Novimmune SA, Geneva, Switzerland and 4Department of Pediatrics, Sapienza, University of Rome, Rome, Italy
ABSTRACT
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 con- trols 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 path- way plays a major role in GF occurring after HSCT. Increased serum levels of IFNγ and CXCL9 represent potential biomarkers useful for early diagno- sis of GF and provide the rationale for exploring the therapeutic/preventive role of targeted neutralization of IFNγ.
Introduction
Graft failure (GF), estimated to occur in 1-5% of cases after myeloablative con- ditioning and in up to 30% of cases after reduced-intensity conditioning (RIC),1 still remains a relevant cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT).2 Despite a slight reduction of its incidence over the last decade, mortality after GF remains as high as 11%.3 To date, in the absence of effective treatment options, re-transplantation, from either the same, or whenever possible, a different donor is considered the treatment of choice.2 Currently identified risk factors for GF include: i) human leukocyte anti- gen (HLA)-disparity and sex mismatch in the donor/recipient pair; ii) presence of
Correspondence:
PIETRO MERLI
pietro.merli@opbg.net
Received: January 7, 2019. Accepted: February 18, 2019. Pre-published: February 21, 2019.
doi:10.3324/haematol.2019.216101
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/11/2314
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haematologica | 2019; 104(11)
ARTICLE