The Effect of Costimulatory and Interleukin 2 Receptor Blockade on Regulatory T Cells in Renal Transplantation

Abstract

Regulatory T cells (Treg) are critical regulators of immune tolerance. Both IL-2 and CD28-CD80/CD86 signaling are critical for CD4+CD25+FOXP3+ Treg survival in mice. Yet, both belatacept (a second-generation CTLA-4Ig) and basiliximab (an anti-CD25 monoclonal antibody) are among the arsenal of current immunotherapies being used in kidney transplant patients. In this study, we explored the direct effect of basiliximab and belatacept on the Tregs in peripheral blood both in the short term and long term and in kidney biopsies of patients with acute rejection. We report that the combined belatacept/basiliximab therapy has no long-term effect on circulating Tregs when compared to a calcineurin inhibitor (CNI)-treated group. Moreover, belatacept-treated patients had a significantly greater number of FOXP3+ T cells in graft biopsies during acute rejection as compared to CNI-treated patients. Finally, it appears that the basiliximab caused a transient loss of both FOXP3+ and FOXP3− CD25+ T cells in the circulation in both treatment groups raising important questions about the use of this therapy in tolerance promoting therapeutic protocols.

Isolated Endarteritis and Kidney Transplant Survival

“…14 It is noteworthy to differentiate our results from the belatacept phase III trial, which showed higher rates of early endarteritis (18% versus 4%) and slightly less DSA (4% versus 7%) but superior renal function and comparable graft survival through 5 years in patients treated with belatacept versus cyclosporin, respectively. [24][25][26] Another study indicated that patients treated with belatacept had more T-regulatory cells in biopsies during rejection compared with patients treated with calcineurin inhibitor, 27 suggesting that belatacept may ease recovery from acute rejection by selective immune regulation. In contrast, most patients in our cohort were on calcineurin inhibitors, and endarteritis unresponsive to anti-T cell therapy was a poor prognostic indicator.…”

Combining therapeutic antibodies using basiliximab and etanercept for severe steroid-refractory acute graft-versus-host disease: A multi-center prospective study

“…Tregs. [24][25][26] Taking into account the potential impacts of basiliximab on Treg function and the well-accepted fact that a complex network of cytokines, cellular receptors, and immune cell subsets resulting in the initiation and maintenance of aGVHD, we speculated that the blockade of multiple effector pathways may ultimately be necessary. To our knowledge, our study is the first prospective, multi-center clinical trial to develop a combined inflammatory cytokine inhibition therapy for SRaGVHD by using basiliximab and etanercept.…”

Tolerance in Kidney Transplantation

“…The efficacy of this treatment to prevent acute rejection is similar to rabbit antithymocyte globulin treatment with fewer side effects (Soulillou et al, 1990). Nowadays it's clearly demonstrated that treatments with anti-IL2R associated with cyclosporin A and steroids ameliorate the survival of the graft and decrease opportunistic infections, but nevertheless with a little more acute rejection (Brennan et al, 2006) and a decrease of Tregs in periphery (Bluestone et al, 2008). Alentuzumab (Campath-1H), a humanized rat monoclonal antibody, binds CD52, a glycoprotein expressed by T and B lymphocytes, monocytes and granulocytes (Xia et al, 1993).…”

“…Treatment with Belatacept permit to have effective immunosuppression, superior renal function and reduced incidence of chronic allograft nephropathy than in patients treated with cyclosporin A . Treatments with Belatacept have no adverse effects on Tregs and even improve their infiltration in the graft (Bluestone et al, 2008). A recent study has tested the immunoregulatory effect of selective CD28 blockade on kidney and heart allograft in primates (ref).…”