Favorably Tipping the Balance between Cytopathic and Regulatory T Cells to Create Transplantation Tolerance

Abstract

Therapeutic application of broadly reactive anti-T cell antibodies can lead not only to potent immunosuppression but also to profound and long-lived T cell depletion. We reasoned that a strategy that almost exclusively targets activated cytopathic donor reactive T cells and spares immunoregulatory networks might prove to be an exceptionally potent and highly selective means of producing long-term engraftment and tolerance. Herein we show that the combined administration of rapamycin and agonist IL-2- and antagonist IL-15-related cytolytic fusion proteins provides for long-term engraftment/tolerance in exceptionally stringent allotransplant models by (1) limiting the early expansion of activated T cells, (2) preserving and even exaggerating their subsequent apoptotic clearance, and (3) further amplifying the depletion of these activated T cells by antibody-dependent mechanisms, while (4) preserving CD4+CD25+ T cell-dependent immunoregulatory networks.

Infiltrating cellular pattern in kidney graft biopsies translates into forkhead box protein 3 up-regulation and p16INK4α senescence protein down-regulation in patients treated with belatacept compared to cyclosporin A

“…Furthermore, GFR was significantly higher at 12 months post-transplant in the belatacept patients with history of acute rejection compared to the CsA patients without acute rejection events during the first posttransplant year [3]. This is in keeping with the concept that all immune responses involve both effector and Tregs, and that it is the balance between these two populations that determines the outcome of the response [14].…”

Homeostatic Proliferation of Lymphocytes Results in Augmented Memory-Like Function and Accelerated Allograft Rejection

“…It has been suggested that during a rejection response, both effector lymphocytes and regulatory T cells are formed and it is the balance between these two populations that determine graft outcome (49). Indeed, higher urinary Foxp3 mRNA levels (presumed to be derived from graft-infiltrating leukocytes leaking into the urine) in patients undergoing rejection are associated with better outcome and long-term graft survival (50).…”

Achieving Donor-Specific Hyporesponsiveness Is Associated with FOXP3+ Regulatory T Cell Recruitment in Human Renal Allograft Infiltrates

“…Recently, it has been shown that more than just acting as a T cell depletion agent, rATG is able to induce a significant increase of Treg in vitro (25), although it has been suggested that Tregs are quite sensitive to elimination by depleting Abs (45). However, it has also pointed out that the relative resistance of Tregs to apoptosis can promote tolerance through preferential depletion of Teffector cells (46,47). In contrast, optimal concentrations of rATG for in vitro generation of Tregs appear to occur at significantly lower levels than those achieved in serum after treatment with standard rATG doses in vivo (42,48).…”