Following Anti-CD25 Treatment, A Functional CD4+CD25+ Regulatory T-Cell Pool Is Present in Renal Transplant Recipients

Abstract

Daclizumab, a humanized antibody directed against the a -chain of the interleukin-2 receptor (CD25), has shown efficacy in the prevention of acute rejection following organ transplantation. However, anti-CD25 therapy can be expected to affect not only alloreactive effector T cells, but also CD4 + CD25 + regulatory T (Treg) cells that are shown to play an important role in the induction of transplantation tolerance. Therefore, the size and function of the Treg pool in human renal allograft recipients after single-dose daclizumab administration was investigated in this study. Approximately 8 weeks after administration, daclizumab was cleared from the circulation and the Treg population then present appeared not different from that observed before transplantation. Functional analysis revealed that the Treg possessed a normal capacity to suppress mixed lymphocyte reactions in vitro. These data indicate that after daclizumab therapy a Treg population, normal in number and function, is present in the peripheral blood of renal transplant recipients.

Tumor infiltrating lymphocytes in ovarian cancer

“…In animal and human studies, anti-CD25 antibodies have been used to deplete Tregs with selective partial depletion reported. 121,122 However, as reported by Kreijveld et al in a study of kidney transplantation, 123 Tregs may be as prominent and functional, if not more, after administration of anti-CD25 antibody therapy. In our human clinical trials using targeted immunotoxins against CD25, transient partial reductions of CD25C Tregs were observed in the blood and tumor of patients with melanoma without significant tumor regression, leading to the postulation that more comprehensive eradication would be necessary to eliminate Treg and achieve clinical benefit.…”

Modulation of tolerance to the transgene product in a nonhuman primate model of AAV-mediated gene transfer to liver

“…Recent findings 27 in humans undergoing kidney transplantation show that 8 weeks after administration of a single dose of daclizumab, a population of CD4 ϩ CD25 ϩ Tregs is present and does not appear to differ from the pre-IS Tregs in its capacity to inhibit lymphocyte proliferation to alloantigens in vitro. The kinetics of Treg depletion and recovery after daclizumab administration in nonhuman primates as shown here closely follows that seen in humans.…”

“…The Treg population returned to levels similar to baseline by week 11 as previously observed in humans receiving a similar IS regimen. 27 The number of CD4 ϩ CD25 ϩ FoxP3 ϩ T cells remained unchanged throughout the study in animals that received no IS (group 1) or MMF and sirolimus (group 3) ( Figure 4A,C).…”

Different Immunosuppressive Combinations on T-Cell Regulation in Renal Transplant Recipients

“…For example, the IL-2 receptor α chain (CD25) is either upregulated in activated T cells, or blocked by agents used for induction therapy such as daclizumab or basiliximab [10]. Many immunosuppressive agents may also have an impact on Tregs by downregulating the production of IL-2 that is required for their expansion [11,12,13,14,15].…”