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)-gamma and CXCL9 (a chemokine specifically induced by IFN.) 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 IFN gamma in HSCT-related GF was further supported by the observation that a rat anti-mouse IFN gamma-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-IFN gamma 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 IFN gamma pathway plays a major role in GF occurring after HSCT. Increased serum levels of IFN gamma 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 IFN gamma.
Role of interferon-gamma in immune-mediated graft failure after allogeneic hematopoietic stem cell transplantation
Merli, Pietro;
2019-01-01
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 controls who had sustained donor cell engraftment. Already at day +3 after transplantation, patients developing GF had serum levels of interferon (IFN)-gamma and CXCL9 (a chemokine specifically induced by IFN.) 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 IFN gamma in HSCT-related GF was further supported by the observation that a rat anti-mouse IFN gamma-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-IFN gamma 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 IFN gamma pathway plays a major role in GF occurring after HSCT. Increased serum levels of IFN gamma 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 IFN gamma.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
