Research Highlights

Abstract

C3 Complement Inhibition Prevents Antibody-mediated Rejection and Prolongs Renal Allograft Survival in Sensitized Nonhuman Primates Schmitz R, Fitch ZW, Schroder PM, et al. Nat Commun. 2021;12:5456. Current therapeutic strategies for desensitization in renal transplantation have shown limited efficacy.1 Because a major downstream effector arm of donor-specific antibody (DSA) is the complement cascade,2 complement inhibition strategies are gaining interest.3 Following C1 and C5 inhibition strategies, the C3 inhibitor Cp40 has recently been added to this field of promising candidates with a successful first-in-human study (NCT03316521) of its derivate AMY-101. In the study from Schmitz et al,4 Cp40 treatment was assessed in a nonhuman primate sensitized renal transplantation model, in which animals received donor skin transplants before the kidney transplant. Induction therapy with rhesus-specific antithymocyte globulin and maintenance therapy with tacrolimus, mycophenolate mofetil, and methylprednisolone were administered with (n = 6) or without (n = 5) peritransplant Cp40 treatment (day –2 to day 14). Although all animals showed a significant DSA increase after transplant, Cp40 treatment reduced acute antibody-mediated rejection and prolonged graft survival clearly (15.5 versus 4 d). Although initial lymphocyte depletion was not affected by Cp40, activation and proliferation proved to be markedly disrupted. Interestingly, virtually no intragraft C3d deposition could be detected during the treatment period with Cp40, which contrasted with controls and treated animals after discontinuation of Cp40. Within the treatment group, there were early (ie, during Cp40 treatment) and late rejectors. Although overall DSA levels were similar, late rejectors had less antibody-mediated rejection and less graft infiltration with CD68+ macrophages in parallel to downregulated complement-related genes. Late rejectors also had higher numbers of CD4+ CD25+ FoxP3+ regulatory T cells 1 wk after transplant, reduced T- and B-cell proliferation, and lower immunoglobulin (Ig)M DSAs with lower complement activation. The authors concluded that because of heterogeneity of IgM DSA levels, Cp40 doses could have been insufficient in animals bearing the highest immunologic burden. These data provide crucial evidence for C3 inhibition in a relevant preclinical model. Notably, overall DSA levels were not predictive of rejection in this study, yet treatment success correlated with IgM DSA load. This study sets the stage for early phase clinical trials of Cp40 in transplantation in which identification and stratification of potential benefit and dosage requirements in patient populations could be incorporated according to IgM DSA levels. An Aged Immune System Drives Senescence and Aging of Solid Organs Yousefzadeh MJ, Flores RR, Zhu Y, et al. Nature. 2021;594:100–105. The decline of immune responses with aging, termed immunosenescence, is linked to increased morbidity and mortality, likely related to reduced immunosurveillance, poor antipathogen immunity, and reduced vaccination responses.1,2 Given the broad role of the immune system in homeostasis, targeting immune cells to influence systemic aging may be a useful strategy for the reversal of age-related tissue pathology. In the landmark study from Yousefzadeh et al in Nature,3 the authors knocked out Ercc1 (which encodes the crucial DNA repair protein endonuclease ERCC1-XPF) in mouse hematopoietic cells, thereby selectively altering senescence in lymphoid organs. The impact of this genetic modification was evaluated in the context of aging. Compared with normal aging in wild-type mice, mutant mice developed peripheral leukopenia in adulthood and overall immune cells decreased in all compartments, as did thymic and splenic weights. Lymphoid tissues were less active and delayed-type hypersensitivity reactions demonstrated decreased innate and adaptive immune functions in older mutant mice, whereas younger ones had similar responses to wild-type littermates. Mutant mice displayed increased oxidative stress in lymphoid tissues and senescence onset in several immune cell subsets when compared with aged wild-type mice. Notably, older mutant mice had systemic changes associated with normal aging measured by DNA damage, oxidative stress, and senescence markers in many solid organ tissues, with peripheral senescence chronologically following immune senescence. Tissue damage appeared in nondeleted organs such as the liver, pancreas, intervertebral discs, brain, and muscles. Accordingly, the lifespan of mutant mice was markedly reduced. Interestingly, some of these effects could be transferred by simple transplantation of aged donor cells into separate recipient mice. Here, transplantation of aged or senescent splenocytes into reporter mice appeared to result in an acceleration of systemic aging and a decreased lifespan. Conversely, adoptive transfer of young wild-type splenocytes was able to attenuate peripheral organ senescence and tissue damage in older recipients. Finally, mechanistic target of rapamycin inhibition with rapamycin mitigated immune senescence characteristics connected with systemic aging. These findings underscore the driving role of immunosenescence in systemic aging, related tissue damage, and fatal outcomes. Additionally, the data highlight some of the molecular mechanisms linking aging and immunosenescence, which may be amenable to therapeutic targeting.