Introduction: Tertialy lymphoid organs (TLTs) are defined as inducible lymphoid tissues that arise in non-lymphoid organs, and chronic sustained inflammation is one of the most important predisposing factors for the development of TLTs. TLTs are found as dense lymphocyte cluster, which is composed of B and T cells with signs of proliferation. Resident fibroblast differentiates into CD21 positive follicular dendritic cells (FDCs), which secret CXCL13 to recruit B cells and support the cluster structurally and functionally. The purpose of this study was to elucidate the clinical relevance of TLTs in transplanted kidney.
Methods: From July 2004 to Dec 2014, 204 kidney transplant recipients who underwent living kidney transplantation (KT) at Akita University Hospital were enrolled in this study. After excluding 23 patients with known risk factors for poor graft outcomes such as acute rejection and/or BK polyoma virus associated nephropathy, 181 patients were finally included. Serial protocol biopsy samples, performed at 0-hr, and 1-, 6-, 12-month after KT, were collected and analyzed for the presence and stages of TLTs. TLTs were categorized into different stages; stage I TLTs, defined as the presence of lymphocyte clusters with signs of proliferation, and stage II TLTs, defined as the additional evidence of CD21+ FDCs. Because some B cell clusters did not express CD21, these structures were denoted as stage I TLTs with B cell cluster.
Results: Although TLTs were found in about 5% of samples in 0-hr biopsy, the prevalence increased to almost 50% at 1-month after KT, and it was maintained at the similar levels for 1-year. Meanwhile, the prevalence of stage II TLTs increased more gradually, from 2% at 1-month to 18% at 1-year post-transplantation. When patients are divided by their TLT staging, those with stage II TLTs in 6- or 12-month biopsies showed progressive decline in graft function over the next 5-years, while those with no or stage I TLTs did not. The use of preoperative rituximab was not associated with the prevalence of overall TLTs, however, it associated with dramatic reduction in the prevalence of both stage II TLT and B cell clusters regardless of biopsy time point. Patients with stage II TLTs in 6- and/or 12-month biopsies showed more severe tubulitis and tubular atrophy scores despite of comparable degree of interstitial inflammation. In subgroup analysis of patients with Banff i score of 0 or 1, the patients with stage II TLTs exhibited progressive graft dysfunction even though the overall degree of interstitial inflammation was mild.
Conclusions: Stage II TLTs predicted progressive graft dysfunction independent from Banff i scores, and finally the use of preoperative rituximab administration was associated with significant reduction in stage II TLT and B cell clusters.
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