Advanced Tertiary Lymphoid Tissues in Protocol Biopsies are Associated with Progressive Graft Dysfunction in Kidney Transplant Recipients

Abstract

Background: Tertiary lymphoid tissues (TLTs) are ectopic lymphoid tissues found in chronically inflamed organs. Although studies have documented TLT formation in transplanted kidneys, the clinical relevance of these TLTs remains controversial. We examined the impacts of TLTs on future graft function using our histological TLT maturity stages and the association between TLTs and Banff pathologic scores. We also analyzed the risk factors for the development of TLTs Methods: Serial protocol biopsy samples (0-hour, 1-, 6-, and 12-months) without rejection were retrospectively analyzed from 214 patients who underwent living donor kidney transplantation. TLTs were defined as lymphocyte aggregates with signs of proliferation and their stages were determined by the absence (stage I) or presence (stage II) of follicular dendritic cells. Results: Only 4% of patients exhibited TLTs at the 0-hour biopsy. Prevalence increased to almost 50% at the 1-month biopsy and then slightly further for 12 months. The proportion of advanced stage II TLTs increased gradually, reaching 19% at the 12-month biopsy. Presence of stage II TLTs was associated with higher risk of renal function decline after transplantation compared to patients with no TLT or stage I TLTs. Stage II TLTs were associated with more severe tubulitis and interstitial fibrosis/tubular atrophy at 12 months and predicted poorer graft function independently from the degree of interstitial inflammation. Pre-transplantation rituximab treatment dramatically attenuated the development of stage II TLTs. Conclusions: TLTs are commonly found in clinically stable transplanted kidneys. Advanced stage II TLTs are associated with progressive graft dysfunction, independent of interstitial inflammation

Detection of infiltrating fibroblasts by single-cell transcriptomics in human kidney allografts

“…The increased accumulation of plasmablast cells with high expression of immunoglobulins in the AK2 biopsy, 8 months after successful treatment of active AMR, may also contribute to the ongoing production of IgG antibodies directed against donor class I and class II HLA we noted in this patient after successful treatment of active AMR ( Table 1 ). None of our biopsies showed histological features of tertiary lymphoid tissues [ 73 ]. To our knowledge, the presence of functionally active long-lived plasma cells in successfully treated active AMR of kidney allograft have not been reported.…”

Increased proportion of follicular helper T cells is associated with B cell activation and disease severity in IgA nephropathy

“…The interaction between Tfh cells and B cells in renal cells can also organize structures that comprise functional germinal centers, defined as tertiary lymphoid organ (TLOs) (8,29,30). Past research has found TLOs in various CKD (31)(32)(33), and TLOs were observed in 37.5% of patients with IgAN (34). Interestingly, we found that Tfh cells co-localized with B cells on renal biopsy tissues of patients with IgAN, suggesting the existence of TLO in IgAN.…”

Tertiary Lymphatic Structures in Primary Hepatic Carcinoma: Controversy Cannot Overshadow Hope

“…TLS are mainly developed in non-lymphoid tissues to deal with various chronic inflammatory diseases including infection, autoimmune diseases, and cancer ( 49 ). However, they are not found in all patients, even those with the same disease ( 50 , 51 ).…”

“…TLS are mainly developed in non-lymphoid tissues to deal with various chronic inflammatory diseases including infection, autoimmune diseases, and cancer (49). However, they are not found in all patients, even those with the same disease (50,51). TLS in human solid tumors are essential for the creation of a favorable immune microenvironment to control tumor development.…”