title: LFA-1-specific therapy prolongs allograft survival in rhesus macaques.
abstract: Outcomes in transplantation have been limited by suboptimal long-term graft survival and toxicities associated with current immunosuppressive approaches. T cell costimulation blockade has shown promise as an alternative strategy to avoid the side effects of conventional immunosuppressive therapies, but targeting CD28-mediated costimulation alone has proven insufficient to prevent graft rejection in primates. Donor-specific memory T (TM) cells have been implicated in costimulation blockade-resistant transplant rejection, due to their enhanced effector function and decreased reliance on costimulatory signaling. Thus, we have tested a potential strategy to overcome TM cell-driven rejection by targeting molecules preferentially expressed on these cells, such as the adhesion molecule lymphocyte function-associated antigen 1 (LFA-1). Here, we show that short-term treatment (i.e., induction therapy) with the LFA-1-specific antibody TS-1/22 in combination with either basiliximab (an IL-2Rα-specific mAb) and sirolimus (a mammalian target of rapamycin inhibitor) or belatacept (a high-affinity variant of the CD28 costimulation-blocker CTLA4Ig) prolonged islet allograft survival in nonhuman primates relative to control treatments. Moreover, TS-1/22 masked LFA-1 on TM cells in vivo and inhibited the generation of alloproliferative and cytokine-producing effector T cells that expressed high levels of LFA-1 in vitro. These results support the use of LFA-1-specific induction therapy to neutralize costimulation blockade-resistant populations of T cells and further evaluation of LFA-1-specific therapeutics for use in transplantation.
authors.affiliation: Emory Transplant Center, Emory University, Atlanta, Georgia, USA.
authors.forename: Idelberto R
authors.initials: IR
authors.lastname: Badell
authors.forename: Maria C
authors.initials: MC
authors.lastname: Russell
authors.forename: Peter W
authors.initials: PW
authors.lastname: Thompson
authors.forename: Alexandra P
authors.initials: AP
authors.lastname: Turner
authors.forename: Tim A
authors.initials: TA
authors.lastname: Weaver
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Robertson
authors.forename: Jose G
authors.initials: JG
authors.lastname: Avila
authors.forename: Jose A
authors.initials: JA
authors.lastname: Cano
authors.forename: Brandi E
authors.initials: BE
authors.lastname: Johnson
authors.forename: Mingqing
authors.initials: M
authors.lastname: Song
authors.forename: Frank V
authors.initials: FV
authors.lastname: Leopardi
authors.forename: Sarah
authors.initials: S
authors.lastname: Swygert
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Strobert
authors.forename: Mandy L
authors.initials: ML
authors.lastname: Ford
authors.forename: Allan D
authors.initials: AD
authors.lastname: Kirk
authors.forename: Christian P
authors.initials: CP
authors.lastname: Larsen
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D057134:Antibodies, Neutralizing / Q000627:therapeutic use*; D002454:Cell Differentiation / Q000276:immunology; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy; D006085:Graft Survival / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory; D007165:Immunosuppression Therapy / Q000379:methods; D016381:Islets of Langerhans Transplantation / Q000276:immunology / Q000473:pathology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology* / Q000378:metabolism; D008253:Macaca mulatta; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology; D014019:Tissue Donors; D014184:Transplantation, Homologous
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D016169:Lymphocyte Function-Associated Antigen-1