4.6 Article

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

期刊

AMERICAN JOURNAL OF TRANSPLANTATION
卷 21, 期 2, 页码 488-502

出版社

WILEY
DOI: 10.1111/ajt.16218

关键词

animal models; murine; basic (laboratory) research; science; clinical research; practice; graft survival; heart transplantation; cardiology; immunosuppressant - fusion proteins and monoclonal antibodies; immunosuppressant - fusion proteins and monoclonal antibodies; belatacept; immunosuppression; immune modulation; T cell biology

资金

  1. National Institutes of Health [RO1AG039449]
  2. German Research Foundation (DFG) [HE 7457/1-1, QU 420/1-1]
  3. Biomedical Exchange Program (BMEP)
  4. Osaka Medical Foundation
  5. Chinese Scholarship Council [201606370196]
  6. Central South University

向作者/读者索取更多资源

Elderly organ transplant recipients have shown reduced effectiveness of CTLA4-Ig treatment compared to young recipients, likely due to decreased CD28 expression in CD4(+)T cells and altered regulation of regulatory T cells (Tregs) with aging. These differences may have unique clinical implications for immunosuppression in elderly transplant recipients.
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.

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