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Allo‐induced Acute‐phase Response; IL‐6 Identifies a Subset of Individuals at Risk for Graft Injury

To the Editor: Acute-phase reactions represent the body’s early innate response to injury or infection. Experimental models suggest that triggering innate immune mechanisms can create a pro-inflammatory environment that promotes ensuing adaptive responses [1]. Detection of IFN-c-secreting cells represents an established read-out of clinically relevant adaptive alloreactivity [2, 3]. Whether allogeneic cells per se can trigger the release of acute-phase cytokines – and hence facilitate expansion of IFN-c-producing alloreactive cells and ⁄ or allo-organ damage independent from injury or infection – remains unknown. Here, we report data from a prospective cohort of 38 renal transplant recipients (for inclusion criteria see Supporting Information). Biopsy-proven rejection was observed in 20 ⁄ 38 study participants, and no evidence of rejection was found in the remainder 18 ⁄ 38 study participants [4]. Alloreactivity was assessed using one-way mixed lymphocyte reactions as previously described (for detailed information on methods see Supporting Information)[5]. The frequency of allo-specific IFN-c-producing cells was assessed in all study participants before transplantation and at 3, 6 and 12 months after transplantation. Allospecific secretion of the innate ⁄ acute-phase cytokines IL-6, TNF-a and IL-1b was measured at these same time points in all study participants with rejection (n = 20) and in 13 ⁄ 18 study participants lacking evidence for rejection. Cytokine levels were related with the occurrence of allograft damage and the frequency of IFN-c-producing cells. Allo-specific secretion of IL-6, TNF-a and IL-1b was detectable already before transplantation in 10 ⁄ 33, 12 ⁄ 33 and 6 ⁄ 33 individuals, respectively. Importantly, prior to transplantation, significantly more IL-6 ‘positive’ individuals were among the group of patients with subsequent rejection (IL-6 ‘positive’ individuals with subsequent rejection: 9 ⁄ 20, IL-6 ‘positive’ individuals with no rejection: 1 ⁄ 13, P = 0.023 in chi square test) (Fig. 1A). No donor-specific secretion of IFN-c was detected at any time point in patients without rejection (n = 18). By contrast, in 6 ⁄ 20 patients with biopsy-proven rejection (clinical or subclinical), donor-specific secretion of IFN-c was measured at least once (Fig. 1B). Important in this context, a positive correlation between pretransplant levels of IL-6 and frequencies of cells producing IFN-c was observed