The Immunosuppressive Effect of CTLA4 Immunoglobulin Is Dependent on Regulatory T Cells at Low But Not High Doses

Abstract

B7.1/2-targeted costimulation blockade (CTLA4 immunoglobulin [CTLA4-Ig]) is available for immunosuppression after kidney transplantation, but its potentially detrimental impact on regulatory T cells (Tregs) is of concern. We investigated the effects of CTLA4-Ig monotherapy in a fully mismatched heart transplant model (BALB/c onto C57BL/6). CTLA4-Ig was injected chronically (on days 0, 4, 14, and 28 and every 4 weeks thereafter) in dosing regimens paralleling clinical use, shown per mouse: low dose (LD), 0.25 mg (≈10 mg/kg body weight); high dose (HD), 1.25 mg (≈50 mg/kg body weight); and very high dose (VHD), 6.25 mg (≈250 mg/kg body weight). Chronic CTLA4-Ig therapy showed dose-dependent efficacy, with the LD regimen prolonging graft survival and with the HD and VHD regimens leading to >95% long-term graft survival and preserved histology. CTLA4-Ig's effect was immunosuppressive rather than tolerogenic because treatment cessation after ≈3 mo led to rejection. FoxP3-positive Tregs were reduced in naïve mice to a similar degree, independent of the CTLA4-Ig dose, but recovered to normal values in heart recipients under chronic CTLA4-Ig therapy. Treg depletion (anti-CD25) resulted in an impaired outcome under LD therapy but had no detectable effect under HD therapy. Consequently, the immunosuppressive effect of partially effective LD CTLA4-Ig therapy is impaired when Tregs are removed, whereas CTLA4-Ig monotherapy at higher doses effectively maintains graft survival independent of Tregs.

Anti-Interleukin-6 Promotes Allogeneic Bone Marrow Engraftment and Prolonged Graft Survival in an Irradiation-Free Murine Transplant Model

“…Grafts were considered to be rejected when less than 10% of the graft remained viable (6). Cervical heterotopic heart transplantation was performed 5 weeks after BMT, as described previously (44). Briefly, the recipient’s right external jugular vein and common carotid artery were everted over a cuff.…”

No augmentation of indoleamine 2,3-dioxygenase (IDO) activity through belatacept treatment in liver transplant recipients

“…This could, hypothetically, involve the blockade of a ‘beneficial’ inhibitory function of CTLA‐4 on T regs , or alternatively the triggering of the B7‐dependent immunomodulatory function of IDO in APCs . While recent evidence suggests that interference with the CTLA‐4 function on T regs depends upon the CTLA‐4 Ig dose , the study presented herein addressed the question whether IDO is triggered as immunomodulatory mechanism in APCs by belatacept.…”

Adoptive Cell Therapy with Tregs to Improve Transplant Outcomes: the Promise and the Stumbling Blocks

“…In another rodent model of single MHC class II-mismatched skin transplantation, CTLA4Ig prevented Treg-dependent tolerance and restored Th1 alloreactivity and allograft rejection [60]. However, in a recent study, prolonged survival of MHC-mismatched heart allografts was Treg-dependent only when CTLA4Ig was used at low doses, whereas the use of high doses of CTLA4Ig was associated with the loss of the Treg-dependent prolonged graft survival [61]. Accordingly, counterproductive effects of CD28 costimulation blockade on Treg in transplantation models can be avoided by refinement of the dose and timing of its administration.…”