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One of the defining lesions of kidney allograft rejection is epithelial deterioration and invasion by inflammatory cells (tubulitis). We examined epithelial changes and their relationship to effector T cells and to CD103/E-cadherin interactions in mouse kidney allografts. Rejecting allografts showed interstitial mononuclear infiltration from day 5. Loss of epithelial mass, estimated by tubular surface area, and tubulitis were minimal through day 7 and severe by day 21. Tubules in day 21 allografts manifested severe reduction of E-cadherin and Ksp-cadherin by immunostaining with redistribution to the apical membrane, indicating loss of polarity. By flow cytometry T cells isolated from allografts were 25% CD103+. Laser capture microdissection and RT-PCR showed increased CD103 mRNA in the interstitium and tubules. However, allografts in hosts lacking CD103 developed tubulitis, cadherin loss, and epithelial deterioration similar to wild-type hosts. The loss of cadherins and epithelial mass was also independent of perforin and granzymes A and B. Thus rejection is characterized by severe tubular deterioration associated with CD103+ T cells but not mediated by CD103/cadherin interactions or granzyme-perforin cytotoxic mechanisms. We suggest that alloimmune effector T cells mediate epithelial injury by contact-independent mechanisms related to delayed type hypersensitivity, followed by invasion of the altered epithelium to produce tubulitis.

Background and purpose Seropositivity for Rheumatoid factors and for antibodies to citrullinated (Cit) protein antigens (ACPA) is the strongest predictor for clinical response to Rituximab (rituximab) in rheumatoid arthritis (RA). The aim of this study was to follow fluctuations of IgG- and IgA-ACPA to multiple individual citrullinated protein epitopes in relation to clinical improvement and resumption of symptoms after rituximab. Methods 16 patients with severe, active RA (DAS28 ≥ 5.1) undergoing initial cycles of rituximab were included. All achieved peripheral B-cell depletion ( Results At Baseline, MFI of IgG- and of IgA-Cit antibodies were strongly correlated (R2 = 0.75; p Conclusion Dissection of the ACPA response after rituximab using multiplex bead array revealed diverse kinetics of autoantibody production and followed several distinct patterns, largely un-related to Cit-epitope specificity. At Relapse, rising levels of ACPA with the same specificities as those at baseline suggested re-expansion of residual Cit-specific memory B cells. As B cell return is mandatory for relapse, and with no marked presence of new autoantibody specificities, potential interactions between newly generated and residual B cells could be exploited for more efficient B cell directed therapies.