Murine Renal Allografts: Spontaneous Acceptance Is Associated with Regulated T Cell-Mediated Immunity

Immune destruction of the graft renal tubules is an important barrier to the long-term function of clinical renal allografts, but the underlying mechanisms remain obscure. CD103—an integrin conferring specificity for the epithelial cell-restricted ligand, E-cadherin—defines a subset of CD8 effectors that infiltrate the graft tubular epithelium during clinical rejection episodes, predicting a causal role for CD103+CD8+ effectors in tubular injury. In the present study, we used rodent transplant models to directly test this hypothesis. Surprisingly, CD8 cells infiltrating renal allografts undergoing unmodified acute rejection did not express significant levels of CD103. However, we demonstrate that a brief course of cyclosporine A to rat renal allograft recipients promotes progressive accumulation of CD103+CD8+ cells within the graft, concomitant with the development of tubular atrophy and interstitial fibrosis. As in the known clinical scenario, graft-associated CD103+CD8+ cells exhibited a T effector phenotype and were intimately associated with the renal tubular epithelium. Treatment with anti-CD103 mAb dramatically attenuated CD8 infiltration into the renal tubules and tubular injury. Mouse studies documented that CD103 expression is required for efficient destruction of the graft renal tubules by CD8 effectors directed to donor MHC I alloantigens. Taken together, these data document a causal role for CD103+CD8+ effectors in promoting tubular injury following allogeneic renal transplantation and identify novel targets for therapeutic intervention in this important clinical problem.

Section: Cd8supporting

confidence: 79%

Critical Role for CD103+CD8+ Effectors in Promoting Tubular Injury following Allogeneic Renal Transplantation

Yuan¹,

El-Asady

Liu

et al. 2005

“…Cytokine neutralization studies clearly demonstrated that TGF-␤1, not IL-10, was the principal mediator of DTH regulation in all the allograft acceptors. A TGF-␤ bias in regulated anti-donor DTH response may reflect conditions unique to tolerance induced by APCs emerging from TGF-␤-rich microenvironments, as previously suggested by studies of mouse kidney transplants (48) and the anterior chamber of the eye (49,50). Other tolerance mechanisms, including IL-10-producing allospecific T regulatory cells (8), may be required to achieve permanent, as opposed to metastable, tolerance.…”

Section: Discussionmentioning

confidence: 97%

Metastable Tolerance to Rhesus Monkey Renal Transplants Is Correlated with Allograft TGF-β1+CD4+ T Regulatory Cell Infiltrates

Torrealba¹,

Katayama

Fechner

et al. 2004

Approaches that prevent acute rejection of renal transplants in a rhesus monkey model were studied to determine a common mechanism of acceptance. After withdrawal of immunosuppression, all 14 monkeys retained normal allograft function for >6 mo. Of these, nine rejected their renal allograft during the study, and five maintained normal function throughout the study period. The appearance of TGF-β1+ interstitial mononuclear cells in the graft coincided with a nonrejection histology, whereas the absence/disappearance of these cells was observed with the onset of rejection. Analysis with a variety of TGF-β1-reactive Abs indicated that the tolerance-associated infiltrates expressed the large latent complex form of TGF-β1. Peripheral leukocytes from rejecting monkeys lacking TGF-β1+ allograft infiltrates responded strongly to donor Ags in delayed-type hypersensitivity trans-vivo assays. In contrast, allograft acceptors with TGF-β1+ infiltrates demonstrated a much weaker peripheral delayed-type hypersensitivity response to donor alloantigens (p < 0.01 vs rejectors), which could be restored by Abs that either neutralized active TGF-β1 or blocked its conversion from latent to active form. Anti-IL-10 Abs had no restorative effect. Accepted allografts had CD8+ and CD4+ interstitial T cell infiltrates, but only the CD4+ subset included cells costaining for TGF-β1. Our data support the hypothesis that the recruitment of CD4+ T regulatory cells to the allograft interstitium is a final common pathway for metastable renal transplant tolerance in a non-human primate model.

“…Immunoregulatory mechanisms involving TGF-␤ and T regs have been identified in rodent recipients that have spontaneously accepted renal allografts, but their association with graft acceptance is poorly understood (3,6). Additionally, TGF-␤-associated immune regulation is only transiently expressed and is not observed in late renal allograft acceptor splenocytes (Ͼ150 days posttransplant) (5).…”

mentioning

confidence: 99%

“…Interestingly, spontaneous renal allograft acceptors display regulation of splenocyte alloresponse to donor Ag. Presence of alloreactive T cells and regulation are demonstrated as delayed-type hypersensitivity (DTH) 3 detectable immune regulation mediated by splenic T cells involving TGF-␤ (3,4). In addition, these allograft acceptors also develop donor-reactive Abs (3,4).…”

mentioning

confidence: 99%

“…Presence of alloreactive T cells and regulation are demonstrated as delayed-type hypersensitivity (DTH) 3 detectable immune regulation mediated by splenic T cells involving TGF-␤ (3,4). In addition, these allograft acceptors also develop donor-reactive Abs (3,4). Given its known immunoregulatory functions, and its association with T regulatory cells (T regs ), involvement of TGF-␤ suggested that regulation associated with spontaneous renal allograft acceptance involved T regs .…”

mentioning

confidence: 99%

See 1 more Smart Citation

Spontaneous Renal Allograft Acceptance Associated with “Regulatory” Dendritic Cells and IDO

Cook¹,

Bickerstaff²,

Wang³

et al. 2008

Self Cite

MHC-mismatched DBA/2 renal allografts are spontaneously accepted by C57BL/6 mice by poorly understood mechanisms, but both immune regulation and graft acceptance develop without exogenous immune modulation. Previous studies have shown that this model of spontaneous renal allograft acceptance is associated with TGF-β-dependent immune regulation, suggesting a role for T regulatory cells. The current study shows that TGF-β immune regulation develops 30 days posttransplant, but is lost by 150 days posttransplant. Despite loss of detectable TGF-β immune regulation, renal allografts continue to function normally for >200 days posttransplantation. Because of its recently described immunoregulatory capabilities, we studied IDO expression in this model, and found that intragraft IDO gene expression progressively increases over time, and that IDO in “regulatory” dendritic cells (RDC) may contribute to regulation associated with long-term maintenance of renal allografts. Immunohistochemistry evaluation confirms the presence of both Foxp3+ T cells and IDO+ DCs in accepted renal allografts, and localization of both cell types within accepted allografts suggests the possibility of synergistic involvement in allograft acceptance. Interestingly, at the time when RDCs become detectable in spleens of allograft acceptors, ∼30% of these mice challenged with donor-matched skin allografts accept these skin grafts, demonstrating progression to “true” tolerance. Together, these data suggest that spontaneous renal allograft acceptance evolves through a series of transient mechanisms, beginning with TGF-β and T regulatory cells, which together may stimulate development of more robust regulation associated with RDC and IDO.