BACKGROUND: Blockade of the CD40-CD40L pathway results in long-term allograft survival but does not prevent chronic rejection. ICOS-ICOSL are members of the CD28-B7 family that play an important role in T-cell activation. METHODS: The authors analyzed the effect of single or combined treatment with an anti-ICOS monoclonal antibody and the fusion molecule CD40 immunoglobulin (Ig) on acute and chronic rejection of heart allografts in rats. RESULTS: Treatment with anti-ICOS resulted in a modest but significant prolongation of allograft survival. Treatment with CD40Ig resulted in long-term graft survival but the cardiac grafts developed chronic rejection lesions. Combined CD40Ig+anti-ICOS treatment led to indefinite graft survival in all recipients and a significant decrease of chronic rejection lesions compared with CD40Ig alone. Importantly, four of the seven CD40Ig+anti-ICOS-treated recipients showed a complete absence of chronic rejection lesions, whereas all of the CD40Ig-treated recipients showed chronic rejection. The CD40Ig+anti-ICOS group also showed significant decreased graft infiltration, decreased antidonor cytotoxic T-lymphocyte activity, and decreased alloantibodies compared with the CD40Ig-treated group. Adoptive transfer of splenocytes indefinitely prolonged allograft survival, whereas those depleted of T cells did not, suggesting the development of T-regulatory mechanisms. CONCLUSIONS. These data indicate that the chronic rejection mechanisms that are CD40-CD40L independent are ICOS-ICOSL dependent. These results were obtained with conservation of cognate immune responses and development of tolerogenic T cells.
BACKGROUND: Blockade of the CD40-CD40L pathway results in long-term allograft survival but does not prevent chronic rejection. ICOS-ICOSL are members of the CD28-B7 family that play an important role in T-cell activation. METHODS: The authors analyzed the effect of single or combined treatment with an anti-ICOS monoclonal antibody and the fusion molecule CD40 immunoglobulin (Ig) on acute and chronic rejection of heart allografts in rats. RESULTS: Treatment with anti-ICOS resulted in a modest but significant prolongation of allograft survival. Treatment with CD40Ig resulted in long-term graft survival but the cardiac grafts developed chronic rejection lesions. Combined CD40Ig+anti-ICOS treatment led to indefinite graft survival in all recipients and a significant decrease of chronic rejection lesions compared with CD40Ig alone. Importantly, four of the seven CD40Ig+anti-ICOS-treated recipients showed a complete absence of chronic rejection lesions, whereas all of the CD40Ig-treated recipients showed chronic rejection. The CD40Ig+anti-ICOS group also showed significant decreased graft infiltration, decreased antidonor cytotoxic T-lymphocyte activity, and decreased alloantibodies compared with the CD40Ig-treated group. Adoptive transfer of splenocytes indefinitely prolonged allograft survival, whereas those depleted of T cells did not, suggesting the development of T-regulatory mechanisms. CONCLUSIONS. These data indicate that the chronic rejection mechanisms that are CD40-CD40L independent are ICOS-ICOSL dependent. These results were obtained with conservation of cognate immune responses and development of tolerogenic T cells.
Authors: Wilson Z Ray; Rahul Kasukurthi; Santosh S Kale; Katherine B Santosa; Daniel A Hunter; Philip Johnson; Ying Yan; Thalachallour Mohanakumar; Susan E Mackinnon; Thomas H Tung Journal: Muscle Nerve Date: 2011-01 Impact factor: 3.217
Authors: Baowei Peng; Peiqing Ye; Bruce R Blazar; Gordon J Freeman; David J Rawlings; Hans D Ochs; Carol H Miao Journal: Blood Date: 2008-06-23 Impact factor: 22.113
Authors: Masahiko Sato; Rainer Storb; Carol Loretz; Diane Stone; Marco Mielcarek; George E Sale; Andrew R Rezvani; Scott S Graves Journal: Transplantation Date: 2013-07-15 Impact factor: 4.939