Mucosal plasma cell barrier disruption during intestine transplant rejection

摘要

Background: Intestinal allograft mucosa undergoes repopulation with host immunocytes. However, critical changes within key immunocyte subsets are not known. Methods: To explain acute cellular rejection after intestine transplantation (ITx) on the basis of altered mucosal immunocytes, rejecting and rejection-free ITx allografts (n=17) were compared with genome-wide expression arrays. Cells identified by cell/lineage-specific genes were evaluated by immunohistochemistry. The corresponding phenotype and donor-specific alloreactivity were characterized in peripheral blood. Time-dependent changes in candidate cell(s) were evaluated in biopsies from an independent cohort of 12 children with ITx. Results: Among 107 differentially expressed genes, three B-cell lineage-specific genes, CCR10, STAP1, and IGLL1, were down-regulated during ITx rejection and were selected for and achieved technical quantitative reverse transcription polymerase chain reaction replication. Down-regulation of the immunoglobulin (Ig)A+ plasma cell-specific CCR10 gene correlated with decreased mature mucosal CD138+ plasma cell numbers in corresponding biopsy specimens (r=0.761, P=0.006) and inversely correlated with enhanced alloreactivity of CD154+ T-cytotoxic memory cells (r=-0.56, P=0.031), which predict acute cellular rejection with high sensitivity. An independent cohort of serial biopsy specimens from 12 ITx recipients (1) confirmed relative CD138+ plasma cell depletion during rejection (P=0.042) and (2) showed increased IgG+-to-IgA+ cell ratios within 4 hr of reperfusion in rejection-prone allografts (P=0.037) and during ITx rejection (P=0.025), compared with rejection-free allografts. No differences existed late after ITx. Increased peripheral IgG+ CD27+ CD19+ memory B cells (P=0.004) were seen during ITx rejection in archived peripheral blood lymphocyte from test and replication cohorts. Conclusions: Protracted depletion of the mucosal CD138+ plasma cell barrier and early mucosal infiltration with memory IgG+ cells characterize the rejection-prone intestine allograft. Mucosal IgA+ plasma cell barrier reconstitution may augur resolution of ITx rejection.