The therapeutic potential of interleukin-2/anti-interleukin-2 antibody complex in cold storage-associated kidney transplantation

The incidence of end-stage renal disease (ESRD) is gradually increasing worldwide, with a 107% increase in the United States from 2000 to 2019.¹ Compared to hemodialysis and peritoneal dialysis, kidney transplantation significantly reduces mortality rates and improves the quality of life for ESRD patients, making it the preferred form of renal replacement therapy. However, the glaring disparity between the demand for kidney donors and their availability persists. Consequently, we have to expand the criteria for using donor kidneys. However, such kidneys are often from older donors, those with hypertension, or those from patients who have undergone cardiopulmonary resuscitation. The short-term recovery and long-term prognosis of these donor kidneys face significant challenges. Among them, delayed graft function (DGF) is a common complication that affects prognosis.² DGF is defined as the requirement for dialysis within the first week following transplantation and is indicative of significant acute tubular necrosis. IRI, which refers to damage caused when blood flow is restored to an ischemic organ, can lead to DGF, primary non-function and even loss of the transplanted kidney, significantly impacting early functional recovery and long-term survival of the transplant.³

In kidney transplantation, the warm and cold ischemic injuries to the transplanted kidney are unavoidable. Warm ischemia time is defined as the duration between the cessation of donor blood supply to an organ and the initiation of cold perfusion, while cold ischemia time refers to the period during which grafts are stored in a cold organ preservation solution.⁴ The mouse kidney transplantation with prolonged cold ischemia time is a suitable model, although it cannot fully replicate the clinical processes of human transplantation. Notably, human kidney grafts can withstand 24 h of cold ischemia, while mouse kidney grafts can tolerate a maximum of 10 h of cold ischemia, with varying degrees of maladaptive repair observed post-transplantation.^{5, 6}

Regulatory T cells (Tregs) represent a subset of CD4+ T cells, which are categorized into three classes based on their origin and differentiation pathways. Among these, Tregs derived from immature T lymphocytes during thymic development, characterized by the CD4+ CD25+ Foxp3+ phenotype, are commonly utilized in research.⁷ The application of Tregs in the field of solid organ transplantation is particularly relevant to the goal of achieving tolerance, aiming to reduce or eliminate the need for immunosuppressive drugs while maintaining tissue repair and managing acute rejection responses. A key challenge in the clinical use of Tregs is how to effectively expand their numbers, whether by increasing the number of endogenous Tregs or through the direct infusion of exogenously expanded Tregs.⁸ Various approaches have been taken to expand Tregs in vitro, including various agonistic strategies involving cytokines and gene transfer methods. However, due to the difficulties in producing and expanding Tregs in vitro, the in vivo expansion of Tregs remains an attractive option for human therapeutic purposes.⁹ Notably, Tregs play a significant role in non-transplant-related renal warm IRI by suppressing acute damage and promoting recovery after IRI.⁷ Therefore, the potential role and mechanisms of Tregs in the cold storage of transplanted kidneys warrant further investigation.

In this study, Jang et al. found that cold IRI in transplanted kidneys can cause severe renal damage, and the exogenous supplementation of interleukin (IL)-2C increases the infiltration of renal Tregs, thereby alleviating acute, subacute and chronic cold IRI-induced renal damage and subsequent fibrosis.¹⁰ The authors found that daily administration of IL-2C from day 5 to day 1 before kidney transplantation significantly reduced blood creatinine and BUN levels, reduced tissue damage and tubular apoptosis and decreased infiltration of CD45+, F4/80 +CD11b+, Gr-1+CD11b+ and CD3+cells. More importantly, post-IRI treatment with IL-2C improved kidney function, enhanced renal regeneration, promoted renal recovery and inhibited renal fibrosis. Dr. Jang et al. further discovered that IL-2C treatment increased the renal expression levels of interferon-γ and IL-10 during cold IRI, and reduced the expression levels of tumour necrosis factor-α, IL-1β and MCP-1. Tregs are crucial for this protection, and Treg depletion by DT treatment exacerbated acute damage and renal inflammation after cold IRI. The evidence provided by this study suggests that using IL-2/anti-IL-2 complexes to expand Tregs in vivo may be a promising approach for treating kidney IRI and other autoimmune diseases.

The study by Dr. Jang et al. explored the protective effects of IL-2C on cold IRI, enhancing our understanding of the mechanisms behind IRI in kidney transplants. However, further work is needed to validate the impact of IL-2C on other T cell subtypes, in addition to its effects on Tregs. While IL-2C has shown protection in rodents against cold IRI, if applied to cases of human DGF, more research is required to better understand the immunological differences and risks between rodents and humans. For example, detecting the cellular levels of Tregs in clinical samples and the effects of IL-2C on human Treg cells could provide insights into their role in graft function. Ultimately, post-transplant acute and chronic immune rejection reactions are crucial factors determining the prognosis of transplanted kidneys. Therefore, the impact of IL-2C on immune rejection reactions is also a crucial factor in determining its clinical translational value and deserves further exploration.

Jiefu Zhu contributed to the conception of the study and reviewed the manuscript. Yao Xia wrote the manuscript.

The authors declare no conflict of interest.