Anti-lymphocyte function-associated antigen-1 monoclonal antibody inhibits CD40 ligand-independent immune responses and prevents chronic vasculopathy in CD40 ligand-deficient mice.
BACKGROUND
Blockade of CD40 ligand (CD40L; CD154, gp39) is a potential treatment for autoimmune disease and allograft rejection. However, CD40L-/- mice are capable of mobilizing cellular immune responses to viral, parasitic, and intracellular bacterial infections as well as rejecting skin grafts with nearly the same efficiency as wild-type mice. CD40L-deficient mice (CD40L-/-) or wild-type mice treated with anti-CD40L develop chronic vasculopathy only 8 weeks after allogeneic heart transplantation. To overcome CD40L-independent immune responses, we used anti-lymphocyte function-associated antigen monoclonal antibody (LFA)-1, which has previously been shown to inhibit CD8+ immune responses.


METHODS
We conducted mixed lymphocyte reactions, cytotoxicity assays, skin transplantation, and vascularized heterotopic heart transplantation in wild-type B6 and CD40L-deficient mice in the presence and absence of anti-LFA-1 to study the effects of anti-LFA-1 in the absence of CD40L signaling.


RESULTS
Anti-LFA-1 inhibited proliferation of naïve CD40L-/- mixed leukocyte reactions and the lysis of donor targets by CD40L-/- cytotoxic T lymphocytes. Anti-LFA-1-treated CD40L-/- mice that received fully MHC-mismatched skin grafts showed significant prolongation of graft survival, with a median survival time of 55 days (mean 66 days) compared with 13 and 21 days in wild-type and CD40L-/- controls, respectively. CD40L-/- mice that received fully MHC-mismatched vascularized heart transplants treated with four doses of 200 microg of anti-LFA-1 at the time of transplantation did not develop any signs of chronic vasculopathy 150 days after transplantation.


CONCLUSIONS
These results indicate that anti-LFA-1 can complement CD40L inhibition in the prevention of undesirable immune responses.
Department of Nephrology and Transplantation, University Hospital, Lund University, Malmö, Sweden.
Matthias
M
Corbascio
Harish
H
Mahanty
Cecilia
C
Osterholm
Zhongquan
Z
Qi
Thomas C
TC
Pearson
Christian P
CP
Larsen
Chris E
CE
Freise
Henrik
H
Ekberg
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D023201:CD40 Ligand / Q000235:genetics / Q000276:immunology*; D002455:Cell Division / Q000276:immunology; D002908:Chronic Disease; D006084:Graft Rejection / Q000276:immunology / Q000628:therapy*; D006085:Graft Survival / Q000276:immunology; D016027:Heart Transplantation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011183:Postoperative Complications / Q000276:immunology / Q000517:prevention & control; D016038:Skin Transplantation; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology; D014184:Transplantation, Homologous; D014652:Vascular Diseases / Q000276:immunology / Q000517:prevention & control* / Q000628:therapy
D000911:Antibodies, Monoclonal; C114320:anti-LFA-1 monoclonal antibody; D023201:CD40 Ligand