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Anti-lymphocyte function-associated antigen-1 monoclonal antibody inhibits CD40 ligand-independent immune responses and prevents chronic vasculopathy in CD40 ligand-deficient mice.

Corbascio, Matthias; Mahanty, Harish; Österholm, Cecilia LU ; Qi, Zhongquan LU ; Pearson, Thomas C; Larsen, Christian P; Freise, Chris E and Ekberg, Henrik LU (2002) In Transplantation 74(1). p.35-41
Abstract
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,... (More)
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. CONCLUSION: These results indicate that anti-LFA-1 can complement CD40L inhibition in the prevention of undesirable immune responses. (Less)
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@article{dd13fc0b-f6c1-4315-9b86-b1193007c24c,
  abstract     = {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. CONCLUSION: These results indicate that anti-LFA-1 can complement CD40L inhibition in the prevention of undesirable immune responses.},
  author       = {Corbascio, Matthias and Mahanty, Harish and Österholm, Cecilia and Qi, Zhongquan and Pearson, Thomas C and Larsen, Christian P and Freise, Chris E and Ekberg, Henrik},
  issn         = {1534-6080},
  keyword      = {Skin Transplantation,Postoperative Complications : prevention & control,Postoperative Complications : immunology,Knockout,Mice,Inbred C57BL,Inbred C3H,Inbred BALB C,Male,Heart Transplantation,Graft Survival : immunology,Graft Rejection : therapy,Chronic Disease,Cell Division : immunology,CD40 Ligand : immunology,CD40 Ligand : genetics,Monoclonal : pharmacology,Antibodies,Graft Rejection : immunology,Animal,Support,Non-U.S. Gov't,T-Lymphocytes,Cytotoxic : cytology,Cytotoxic : immunology,Transplantation,Homologous,Vascular Diseases : immunology,Vascular Diseases : prevention & control,Vascular Diseases : therapy},
  language     = {eng},
  number       = {1},
  pages        = {35--41},
  publisher    = {Lippincott Williams & Wilkins},
  series       = {Transplantation},
  title        = {Anti-lymphocyte function-associated antigen-1 monoclonal antibody inhibits CD40 ligand-independent immune responses and prevents chronic vasculopathy in CD40 ligand-deficient mice.},
  volume       = {74},
  year         = {2002},
}