CTLA4-Ig prolongs graft survival specifically in young but not old mice

Elderly organ transplant recipients have remained underrepresented in clinical trials, despite representing a rapidly growing population. Here, we assessed age-specific effects of CTLA4-Ig (cytotoxic T-lymphocyte antigen 4-Ig), a fusion protein blocking costimulatory signaling between antigen-presenting cells and T cells through CD28. Cardiac allografts in young mice (2-3 months) treated with CTLA4-Ig survived indefinitely, whereas 80% of old recipients (18 months) had lost their graft after 100 days. CTLA4-Ig was also significantly less effective in older recipients of skin transplants. CTLA4-Ig reduced CD4⁺ central memory and effector memory T cells and diminished systemic interferon-gamma levels only in young recipients. These differences corresponded to a reduced expression of CD28 on antigen-experienced CD4⁺ T cells in old mice. In support, adoptive transfer of old CD4⁺ T cells that were transfected with a lentiviral vector inducing constant expression of CD28 accelerated the rejection of allogeneic skin grafts in young RAG2^–/– recipient mice. Regulatory T cells (Tregs), in contrast, demonstrated an increased expression of CD28 with aging and CTLA4-Ig treatment in old recipients resulted in reduced frequencies, compromised proliferation, and diminished suppressive capacity of Tregs. These findings may prove to have unique clinical consequences for immunosuppression in the growing population of elderly transplant recipients.