Targeting Leukocyte Integrin CD11b/CD18 to Improve Transplant Outcomes: A Big Step Forward

Despite advances in short-term kidney allograft survival, long-term graft survival remains an important opportunity for improvement. The 5-y worldwide survival of deceased donor transplants is 70%–90% and the 10-y survival drops to 50%–70%.1 Ischemia/reperfusion injury (IRI) and allograft rejection are attractive targets to improve transplant outcomes.2 The pathophysiology of IRI is multifactorial and complex, involving inflammation, apoptosis, metabolic derangements, and many other pathways.3 The microvascular injury during IRI is characterized by leukocyte/endothelial interactions that involve neutrophils, macrophages, T and B cells.4 There are many overlapping features in the microvascular injury during IRI and allorejection. The deleterious leukocyte-endothelial adhesion pathways that underlie microvascular injury have been extensively studied.5 A fundamental advance was the discovery and cloning of CD11b, a member of the integrin receptor family that forms the heterodimer complement receptor 3 (CD11b/CD18).5 This molecule is expressed on neutrophils, macrophages, and monocytes. CD11b+ cells interact with intercellular adhesion molecule 1 expressed on injured endothelial cells to infiltrate the injury site, perform phagocytosis, and release inflammatory cytokines that activate and recruit other immune cells (Figure 1). In this issue of Transplantation, Dehnadi et al6 reported that monoclonal antibody 107 (mAb107) to CD11b markedly attenuated ischemia injury and extended allograft survival, with diminished rejection in Cynomolgus male monkeys undergoing kidney transplantation. The right kidney was clamped for 20 min in the donor, cold flushed, and then underwent 100 min of static cold storage. This was followed by transplantation into the right kidney-nephrectomized right pelvis of the recipient. The recipient’s left kidney was kept intact during early management, then had its ureter ligated on day 10. The immunosuppression protocol in this study was tacrolimus, targeting trough levels of 9–10 ng/mL, with rapidly tapering methylprednisolone. Control animals received tacrolimus and steroids, whereas mAb to CD11b (mAb107) was administered before allograft revascularization to both recipients and donors in group A and, importantly, only to recipients in group B. Unlike other antibodies to leukocyte integrins, mAb 107 is a specific blocker without activating effects. Major histocompatibility complex mismatch was >5 of 10 in each group. Surviving animals were euthanized on day 104. Allograft survival was markedly prolonged in both groups A and B compared with the controls, which all lost their allografts by day 30. Donor-specific antibody elevation was attenuated in group A, presumed due to the mAb107 effect on suppressing proinflammatory cytokines or the CD40/CD154 axis. Protocol biopsies on day 10, evaluated histologically using the Banff classification, as well as immunostaining and with wide gene profiling by Nanostring technology, demonstrated decreased infiltration of neutrophils, macrophage, and T cells, with reduced capillary vasculitis in the mAb107 groups. There are a number of important findings in this study. First, administering mAb107 against CD11b, either pre- or posttransplant, led to a marked allograft survival when coupled with the clinically designed regimen of tacrolimus and tapering steroids. This has major human translational significance, given that this study was performed in nonhuman primates. Many positive studies in rodents have failed to translate to humans, so nonhuman primate studies are much more likely to impact patients. Second, targeting the microvascular injury by a specifically blocking and nonactivating antibody to CD11b on neutrophils and macrophages both attenuated innate immunity during IRI but also had a marked effect on subsequent allograft rejection. This reveals that CD11b is a key central molecule that links these 2 processes. However, it is concerning that one of the monkeys that received mAb107 developed sepsis and died. Blocking CD11b may well have prevented neutrophil migration to a site of infection site and worsened sepsis. However, paradoxically, CD11b has been shown to downregulate high mobility group box 1 protein, which decreases sepsis.7 Furthermore, the Dehnadi study was limited in that mechanistic evaluation of infiltrating leukocytes was not performed by more advanced approaches, including spectral flow cytometry or single-cell mRNA sequencing. In conclusion, this article represents an important advance and a “big step” toward developing new therapeutics for organ transplantation in humans. Given the precision of the targeted approach, the study also extends our understanding of the pathogenesis of IRI and allograft rejection. These promising data support the study of mAb107, and other CD11b-directed therapeutics in clinical trials for human allotransplantation as well as the rapidly moving field of xenotransplantation.FIGURE 1.: The leukocyte integrin CD11b during kidney ischemia reperfusion and allograft rejection. CD11b+ cells interact with ICAM-1 and other ligands on injured endothelial cells to amplify microvascular injury, infiltrate into injured tissue, recruit and activate other immune cells to amplify the inflammation. Targeting CD11b with mAb107, as described by Dehnadi et al,6 presents an attractive approach to attenuate both IRI and allograft rejection. CD11b structure in the middle is adopted and modified from the publication.8 ICAM-1, intercellular adhesion molecule 1; IRI, ischemia/reperfusion injury; mAb107, monoclonal antibody to CD11b.