title: Combined costimulatory and leukocyte functional antigen-1 blockade prevents transplant rejection mediated by heterologous immune memory alloresponses.
abstract: BACKGROUND
  Recent evidence suggests that alloreactive memory T cells are generated by the process of heterologous immunity, whereby memory T cells arising in response to pathogen infection crossreact with donor antigens. Because of their diminished requirements for costimulation during recall, these pathogen-elicited allocrossreactive memory T cells are of particular clinical importance, especially given the emergence of costimulatory blockade as a transplant immunosuppression strategy.
  
  
  METHODS
  We used an established model of heterologous immunity involving sequential infection of a naïve C57BL/6 recipient with lymphocytic choriomeningitis virus and vaccinia virus, followed by combined skin and bone marrow transplant from a BALB/c donor.
  
  
  RESULTS
  We demonstrate that coupling the integrin antagonist anti-leukocyte functional antigen (LFA)-1 with costimulatory blockade could surmount the barrier posed by heterologous immunity in a fully allogeneic murine transplant system. The combined costimulatory and integrin blockade regimen suppressed proliferation of alloreactive memory T cells and attenuated their cytokine effector responses. This combined blockade regimen also promoted the retention of FoxP³⁺ Tregs in draining lymph nodes. Finally, we show that in an in vitro mixed lymphocyte reaction system using human T cells, the combination of belatacept and anti-LFA-1 was able to suppress cytokine production by alloreactive memory T cells that was resistant to belatacept alone.
  
  
  CONCLUSIONS
  As an antagonist against human LFA-1 exists and has been used clinically to treat psoriasis, these findings have significant translational potential for future clinical transplant trials.
authors.affiliation: Emory Transplant Center, Emory University, Atlanta, GA, USA.
authors.forename: William H
authors.initials: WH
authors.lastname: Kitchens
authors.forename: Divya
authors.initials: D
authors.lastname: Haridas
authors.forename: Maylene E
authors.initials: ME
authors.lastname: Wagener
authors.forename: Mingqing
authors.initials: M
authors.lastname: Song
authors.forename: Mandy L
authors.initials: ML
authors.lastname: Ford
mesh_terms: D000818:Animals; D060887:B7 Antigens / Q000037:antagonists & inhibitors*; D016026:Bone Marrow Transplantation / Q000276:immunology; D019013:CD40 Antigens / Q000037:antagonists & inhibitors*; D023201:CD40 Ligand / Q000037:antagonists & inhibitors*; D006084:Graft Rejection / Q000517:prevention & control*; D006085:Graft Survival; D006801:Humans; D007156:Immunologic Memory; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation; D016169:Lymphocyte Function-Associated Antigen-1 / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016038:Skin Transplantation / Q000276:immunology; D014184:Transplantation, Homologous
chemical_list: D060887:B7 Antigens; D019013:CD40 Antigens; D016169:Lymphocyte Function-Associated Antigen-1; D023201:CD40 Ligand