Costimulation Blockade followed by a 12-Week Period of Cyclosporine A Facilitates Prolonged Drug-Free Survival of Rhesus Monkey Kidney Allografts

CD40L antibodies have proven to be powerful immunosuppressive agents in nonhuman primates but unfortunately perturb blood coagulation. Neither the therapeutic nor the prothrombotic mechanism of anti-CD40L is defined sufficiently to determine whether these effects can be uncoupled. Recent evidence suggests that the Fc region of anti-CD40L antibodies interacting with Fc receptors plays an important role in stabilizing platelet aggregates. An Fc-disabled, aglycosylated anti-CD40L heavy chain variant was therefore created to determine whether it might still be useful in promoting transplantation tolerance. In a number of mouse models an engineered aglycosyl anti-CD40L recapitulated the effects of the intact anti-CD40L antibody in tolerance protocols involving transplantation of allogeneic bone marrow and skin. In contrast, another anti-CD40L variant with a conventional rat c 2b heavy chain was less effective in ensuring long-term skin graft survival, possibly associated with its faster clearance from the circulation. These results show that short pulses of anti-CD40L antibody therapy may still be useful in tolerance protocols even when the Fc region is disabled.

Section: Discussionmentioning

confidence: 52%

Fc-Disabled Anti-Mouse CD40L Antibodies Retain Efficacy in Promoting Transplantation Tolerance

Daley¹,

Cobbold²,

Waldmann³

2008

“…Finally, in the previous kidney transplant experiment (22) (29), and a monthly 4D11 administration at 40 mg/kg was unable to prevent rejection in our earlier study (22). (10), while the treatment with anti-CD40 mAb, ch5D12, did not (33 (20), while this was not the case with the other antihuman CD40 mAb, ch5D12 (19). Along with the peripheral B-cell reduction, suppression of germinal center formation in the spleen and lymph nodes was noted at the time of autopsy in some of the 4D11-treated monkeys, especially when administered at higher doses.…”

Section: Immunohistological Study: Irrespective Of the Dose And Duratmentioning

confidence: 99%

A Human Anti-CD40 Monoclonal Antibody, 4D11, for Kidney Transplantation in Cynomolgus Monkeys: Induction and Maintenance Therapy

Aoyagi

Yamashita

Suzuki

et al. 2009

Blockade of CD40-CD154 signaling pathway is an attractive strategy to induce potent immunosuppression and tolerance in organ transplantation. Due to its strong immunosuppressive effect shown in nonhuman primate experiments, anti-CD154 monoclonal antibodies (mAbs) have been tried in clinical settings, but it was interrupted by unexpected thromboembolic complications. Thus, inhibition of the counter molecule, CD40, has remained an alternative approach. In the previous preliminary study, we have shown that 4D11, a novel fully human anti-CD40 mAb, has a fairly potent immunosuppressive effect on kidney allograft in nonhuman primates. In this study, we aimed to confirm the efficacy and untoward events of the 2-week induction and 180-day maintenance 4D11 treatments. In both, 4D11 significantly suppressed T-cell-mediated alloimmune responses and prolonged allograft survival. Addition of weekly 4D11 administration after the induction treatment further enhanced graft survival. Complete inhibition of both donor-specific Ab and anti-4D11 Ab productions was obtained only with higherdose maintenance therapy. No serious side effect including thromboembolic complications was noted except for a transient reduction of hematocrit in one animal, and decrease of peripheral B-cell counts in all. These results indicate that the 4D11 appears to be a promising candidate for immunosuppression in clinical organ transplantation.

“…The biopsies and the necropsy materials were scored for rejection according to the Banff '97 criteria (16). Results of these studies have been reported previously (9)(10)(11)15,(17)(18)(19)(20). Biopsies were divided into groups according to the presence or absence of rejection and subsequently according to the type of rejection.…”

Section: Animalsmentioning

confidence: 99%

Expression Patterns of Regulatory T-Cell Markers in Accepted and Rejected Nonhuman Primate Kidney Allografts

Haanstra

Wubben

Korevaar

et al. 2007

The identification of FOXP3 expressing cells in recipients of an allograft, in particular inside the graft itself, may help to define criteria for immunosuppressive drug withdrawal. We therefore examined expression patterns of several regulatory T-cell (Treg) markers in kidney biopsies and kidney tissues taken at the time of graft rejection from monkeys treated with a CD40, a CD86, CsA, a combination of these or after drug withdrawal. We conclude that the presence of intragraft FOXP3+ cells is not confined to tolerated grafts, but should be considered as part of the normal immune response during rejection.