PD-1 deficiency augments bone marrow failure in a minor-histocompatibility antigen mismatch lymphocyte infusion model.

Abstract

Although PD-1 blockade has revolutionized cancer immunotherapy, immune-related adverse events (irAEs) present life-threatening complications. Recent reports of aplastic anemia (AA) as irAEs implicate PD-1/PD-L1 as important in preventing immune-mediated destruction of the hematopoietic niche. Infusion of PD-1-deficient (PD-1 knockout [KO]) lymph node (LN) cells into minor-antigen mismatched mice resulted in early mortality, as well as more severe bone marrow (BM) hypoplasia, anemia, and BM microarchitecture disruption in PD-1 KO LN-infused mice relative to mice that received B6 LN cell infusion. Mice that received PD-1 KO LN cells had more CD8+ T-cell infiltration of the BM and greater expansion of H60-specific CD8+ T cells than did their B6 LN-infused counterparts. In the spleen, CD8+ T cells were skewed to an effector memory phenotype, suggesting accelerated differentiation of PD-1 KO T cells. Our data suggest that PD-1 dysregulation has a role in murine BM failure and vigilance in irAE monitoring may be desirable to treat early AA and related cytopenias.

• Authors: Maile K Hollinger, Valentina Giudice, Nicole A Cummings, Guillermo Rivell, Hansheng Zhang, Sachiko Kajigaya, Keyvan Keyvanfar, Jichun Chen, Xingmin Feng, Neal S Young
• Journal: Experimental hematology (Exp Hematol) Vol. 62 Pg. 17-23 (06 2018) ISSN: 1873-2399 [Electronic] Netherlands
• PMID: 29524567 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)
• Copyright: Published by Elsevier Inc.

Chemical References

• Minor Histocompatibility Antigens
• Pdcd1 protein, mouse
• Programmed Cell Death 1 Receptor

Topics

• Anemia, Aplastic (etiology, pathology)
• Animals
• Animals, Congenic
• Bone Marrow (pathology)
• CD8-Positive T-Lymphocytes (immunology)
• Disease Models, Animal
• Immunologic Memory
• Lymph Nodes (cytology)
• Lymphocyte Transfusion (adverse effects)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Minor Histocompatibility Antigens (immunology)
• Programmed Cell Death 1 Receptor (deficiency, physiology)
• Radiation Chimera
• Spleen (pathology)
• T-Lymphocyte Subsets (immunology)