Tubulitis and Epithelial Cell Alterations in Mouse Kidney Transplant Rejection Are Independent of CD103, Perforin or Granzymes A/B

Abstract

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.

The Early Course of Kidney Allograft Rejection: Defining the Time When Rejection Begins

“…Interstitial inflammation is established by day 5 post transplant, followed later by tubulitis and epithelial deterioration (1). Tubulitis is preceded by molecular changes of the epithelium (3,4), which are readily apparent by days [5][6][7], and even earlier by sophisticated methods (3,4). The (2,11,12).…”

Defining the Canonical Form of T-Cell-Mediated Rejection in Human Kidney Transplants

“…ligand-has no effect on the development of the diagnostic TCMR lesions in mouse kidney allografts (11,12). (14,15).…”

Serine Protease Inhibitor-6 Inhibits Granzyme B–Mediated Injury of Renal Tubular Cells and Promotes Renal Allograft Survival

“…This concept may provide insight into allograft rejection injury because there have been disparate results regarding the role of effector T-cell expression of perforin-granzyme in mediating kidney allograft rejection. In previous studies, the absence of perforin-granzyme in recipient effector cells did not prevent tubular injury or rejection but these studies used ''non-lifesupporting'' murine renal transplant models and multiple effector mechanisms apart from perforin-granzyme provide redundant pathways of rejection in vivo (10,11). Moreover, transcript levels of perforin and granzyme B were upregulated in grafts after transplantation which supports a potential role for perforin-granzymeYmediated cytotoxicity (10).…”