Inhibition of Alloantigen‐Primed Memory CD4⁺ and CD8⁺ T Cells by Hematopoietic Chimerism in Mice

Abstract

Donor‐reactive memory T cells present a special hurdle in transplantation. Although hematopoietic chimerism is effective for inducing donor‐specific tolerance, the effects on memory T cells are unclear. Here, we induced stable chimerism and tolerance in mice (Tolerance group, n = 6) by donor‐specific transfusion (DST) plus anti‐CD154 monoclonal antibody (mAb), avoiding the toxic myeloablative conditioning treatment to assist bone marrow transplantation (DST/aCD154&BMTx). We then transferred memory CD4+ or CD8+ T cells from donor antigen primed mice to the tolerance‐induced recipients 4 days after heart transplantation (Tol/CD4+ Tm group and Tol/CD8+ Tm group, n = 6, respectively), but neither of these memory T‐cell subsets had an effect on the permanent graft survival (median survival time > 100 days). The unaltered rate of memory T cells in spleen and anergy to donor antigen in vitro demonstrated that these memory T cells were well controlled. The chimerism‐promoting protocol DST/aCD154&BMTx produced an immune environment that included high levels of regulatory T cells (Tregs), microchimerism and TGF‐β, all of which may act in suppressing the donor‐reactive memory CD4+ or CD8+ T cells. These findings have potentially important implications for designing approaches to suppressing memory T cells for success of transplantation.

Permanent CNI Treatment for Prevention of Renal Allograft Rejection in Sensitized Hosts Can Be Replaced by Regulatory T Cells

“…Preclinical studies demonstrated promising data on the replacement of calcineurin inhibitors (CNI) by less nephrotoxic immunosuppressive drugs, such as mTOR inhibitors or costimulatory blockade, or even induction of tolerance. Most promising results came from T(/B)-cell depletion and costimulatory blockade, alone or in combination with hematopoetic stem cell transplantation (2)(3)(4)(5)(6).…”

“…prolonged ischemia, donor age, chronic diseases, HLA mismatch), the recipients immunological history is a key factor determining the individual responsiveness to an allograft (6). Memory T cells (T mem ) that cause accelerated graft rejection develop through previous transplantations, blood transfusions, and pregnancies, but also through exposure to environmental antigens (heterologous immunity) (17,18).…”