HLA-G dimer targets Granzyme B pathway to prolong human renal allograft survival

FASEB J. 2019 Apr;33(4):5220-5236. doi: 10.1096/fj.201802017R. Epub 2019 Jan 8.


Human leukocyte antigen G (HLA-G), a nonclassic HLA class Ib molecule involved in the maintenance of maternal tolerance to semiallogeneic fetal tissues during pregnancy, has emerged as a potential therapeutic target to control allograft rejection. We demonstrate here that the level of soluble HLA-G dimer was higher in a group of 90 patients with a functioning renal allograft compared with 40 patients who rejected (RJ) their transplants. The HLA-G dimer level was not affected by demographic status. One of the potential mechanisms in tissue-organ allograft rejection involves the induction of granzymes and perforin, which are the main effector molecules expressed by CD8+ cytotoxic T lymphocytes and function to destroy allogeneic transplants. Using genomics and molecular and cellular analyses of cells from T-cell-mediated RJ and nonrejected kidney transplant patients, cells from leukocyte Ig-like receptor B1 (LILRB1) transgenic mice, humanized mice, and genetically engineered HLA-G dimer, we demonstrated a novel mechanism by which HLA-G dimer inhibits activation and cytotoxic capabilities of human CD8+ T cells. This mechanism implicated the down-regulation of Granzyme B expression and the essential involvement of LILRB1. Thus, HLA-G dimer has the potential to be a specific and effective therapy for prevention of allograft rejection and prolongation of graft survival.-Ajith, A., Portik-Dobos, V., Nguyen-Lefebvre, A. T., Callaway, C., Horuzsko, D. D., Kapoor, R., Zayas, C., Maenaka, K., Mulloy, L. L., Horuzsko, A. HLA-G dimer targets Granzyme B pathway to prolong human renal allograft survival.

Keywords: HLA-G; human kidney transplantation; humanized mouse.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Antigens, CD / metabolism
  • CD8-Positive T-Lymphocytes / metabolism
  • Concanavalin A / pharmacology
  • Female
  • Flow Cytometry
  • Graft Rejection
  • Graft Survival
  • Granzymes / metabolism*
  • HLA-G Antigens / metabolism*
  • Humans
  • Kidney Transplantation
  • Leukocyte Immunoglobulin-like Receptor B1 / antagonists & inhibitors
  • Leukocyte Immunoglobulin-like Receptor B1 / metabolism
  • Mice
  • Real-Time Polymerase Chain Reaction
  • T-Lymphocytes / metabolism


  • Antigens, CD
  • HLA-G Antigens
  • LILRB1 protein, human
  • Leukocyte Immunoglobulin-like Receptor B1
  • Concanavalin A
  • Granzymes