The long-term outcome of kidney allograft transplants has not substantially improved over the past 2 decades despite significant advancements in graft survival within the first year posttransplantation as a result of improved immunosuppression.1 A number of factors have been identified as affecting graft outcomes within the first year, including the quality of the donor graft, delayed graft function, and presensitization of the recipient, whereas the cause for late graft loss is less well understood and may be driven by both alloantigen-dependent as well as alloantigen-independent factors.2,3 Cippà et al4 used a transcriptomic approach on serial protocol biopsies of kidney transplant recipients to identify a correlation between the initial response to kidney injury and a late B cell signature that unexpectedly develops even in the absence of alloantigen.
Transcription profiling of protocol biopsies from 42 kidney allografts in the first-year posttransplantation revealed a cluster of biopsies with elevated expression of genes associated with fibrosis, immunity, and B cells. Because fibrosis and inflammation are features that can lead to chronic organ damage,5,6 the authors referred to this group of patients as the maladaptive injury repair group (MIR group), and noted that this group displayed lower renal function and higher Banff histological scores related to chronic kidney damage. Furthermore, this MIR group substantially overlapped with those that had increased B cell-associated genes. These findings raised 2 nonexclusive possible explanations: (1) that the host B cell response drove MIR or (2) that fibrosis and inflammation triggered the recruitment of B cells into the kidney allograft.
To distinguish between these possibilities, the authors examined the transcriptional response in the same kidney by 3 months posttransplantation when renal function was comparable between the MIR and non-MIR groups and before the development of a prominent B cell signature. Notably, the MIR group expressed higher levels of genes associated with acute kidney injury and repair, thus supporting the hypothesis that the maladaptive injury repair was driving by the recruitment of B cells. In accordance, the majority of genes previously identified to be associated with acute rejection7 were only minimally upregulated, while a small subset of 10 genes associated with innate immunity were significantly elevated in the MIR group.
To further test the hypothesis that early kidney injury recruited B cells, the authors turned to a mouse model of ischemia/reperfusion injury (IRI) that resulted in a dysfunctional repair process eventually leading to chronic kidney disease. By 6–12 months post-IRI, a prominent T and B lymphocyte signature was detected, and lymphocytes were observed to be organized into large clusters, reminiscent of ectopic lymphoid structures,8 around small arteries and between renal tubules that expressed markers of unresolved tubular injury. Examination of the larger aggregates revealed B cell zones with proliferating B cells embedded in a network of CD21+/Cxcl13+ follicular dendritic cells, reminiscent of mature germinal centers. Importantly, by 28 days post-IRI when the acute and chronic inflammatory responses overlapped, myeloid cells were the predominant infiltrating cells expressing a cluster of cytokines including those involved with lymphocyte homing, which were also elevated by 6 months post-IRI. The authors concluded that even in the absence of foreign antigens, adaptive immunity can be an intrinsic component of dysfunctional kidney repair.
T cells accumulating in post-IRI kidneys were largely nonconventional TCRαβ+CD4−CD8− (double negative), resembling T cells that have previously been shown to be enriched in old mice and kidney resident T cells.9 Intrarenal B cells were massively expanded, transcriptional analysis suggested a progressive differentiation into plasma cells, and phenotypic analyses confirmed the presence of CD19+/lowB220−CD126+Cxcr4+ cells reminiscent of plasma cell precursors producing autoantibodies and identified in kidneys with lupus disease.10 B cell receptor repertoire analysis confirmed the expansion of polyclonal B cells with an enrichment in a limited number of dominant clones within IRI kidneys. Finally, plasma collected by 16–18 months post-IRI demonstrated a significant increase in autoantibodies. Thus, even in the absence of foreign antigens, IRI-induced kidney damage can elicit an intrarenal B cell response with an accumulation of circulating autoantibodies, raising the possibility that transplanted allogeneic kidneys that suffer IRI-induced damage may allow for the intrarenal accumulation of both autoreactive and alloreactive B cells.
A substantial body of clinical literature has suggested a role for B cells and donor-specific antibodies (DSAs) during late immune responses that result in chronic allograft loss.2 However, mechanisms initiating these B cell responses have not been fully characterized. The study by Cippà et al4 raises the intriguing possibility that early kidney injury initiates a process of inflammation and dysfunctional tissue repair associated with an accumulation of innate myeloid cells that secrete chemokines orchestrating the recruitment and organization of B cells into functional germinal centers within the kidney. In these germinal centers, B cells proliferate and differentiate into antibody-secreting cells that produce autoreactive antibodies, further aggravating dysfunctional tissue repair. In allogeneic kidney transplants, alloreactive B cells may be recruited into the allograft to produce DSA (Figure 1).
If this model is correct, it may explain why intervening with humoral responses in patients presenting with DSA and pathological features of chronic rejection would likely be too late to be effective. Indeed, this model points to new therapeutic approaches directed at mitigating the early dysfunctional repair process to prevent chronic rejection. These observations also suggest that early markers of genes associated with acute kidney injury and repair (eg, LCN2, SOX9, ALDH2A1), fibrosis (eg, COL1A1, DPT, MMP7), and innate immunity (eg, CD52, CXCL10, CCL21) may identify recipients that are at higher risk for developing chronic rejection and should therefore receive a more intensive clinical surveillance. Alternatively, these patients may benefit from novel interventions that are aimed at diminishing early kidney injury or enhancing tissue repair.
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Indeed, this model points to new therapeutic approaches directed at mitigating the early dysfunctional repair process to prevent chronic rejection.