Evidence of Indirect Allorecognition in Long-Term Human Renal Transplantation

Coelho, Verônica; Spadafora-Ferreira, Mônica; Marrero, Idania; Fonseca, J; Portugal, Karina; Kalil, Jorge

doi:10.1006/clim.1998.4626

Cited by 13 publications

(6 citation statements)

References 31 publications

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“…On the other hand, MHC‐allopeptides have been used to induce tolerance in experimental transplantation models, suggesting that the indirect pathway of allorecognition also participates in the induction of tolerance [12, 13]. In addition, we and others have observed donor indirect allorecognition in renal transplant patients, irrespective of rejection [14–16]. We also observed predominant interleukin (IL)‐10 production induced by indirect alloreactivity to donor human leucocyte antigen (HLA)‐DR mismatched peptides, in renal transplant patients without rejection [17].…”

Section: Introductionmentioning

confidence: 77%

CD4⁺CD25⁺Foxp3⁺ Indirect Alloreactive T cells from Renal Transplant Patients Suppress Both the Direct and Indirect Pathways of Allorecognition

et al. 2007

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Alloreactive T cells recognize donor antigens by two routes: direct and indirect pathways of allorecognition. Although the direct pathway is reported to be dominant in allograft rejection, indirect allorecognition also plays an important role. Indirect alloreactivity is also observed in renal transplant patients irrespective of rejection. Previously we showed a predominance of interleukin (IL)‐10 induced by indirect allorecognition of donor human leucocyte antigen (HLA)‐DR peptides, suggesting the existence of indirect alloreactive T cells displaying regulatory activity. In the present work, our objective was to characterize these regulatory T cells. We detected indirect alloproliferation of peripheral blood mononuclear cells (PBMC) from renal transplant patients, induced by donor HLA‐DR peptides, dependent on IL‐4 or IL‐10, suggesting regulatory activity as part of the alloreactive T‐cell repertoire. PBMC‐derived indirect alloreactive T‐cell lines were established and produced both inflammatory and regulatory cytokines. We showed that two of these T‐cell lines which were able to inhibit both direct and indirect alloproliferation of another T‐cell line from the same patient presented a CD4+CD25+Foxp3+ T‐cell population. These data support the idea that indirect alloreactive T cells may also have regulatory activity and may contribute to the maintenance of the human renal allograft.

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Section: Introductionmentioning

confidence: 77%

CD4⁺CD25⁺Foxp3⁺ Indirect Alloreactive T cells from Renal Transplant Patients Suppress Both the Direct and Indirect Pathways of Allorecognition

et al. 2007

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“…Because indirect priming is dependent on antigen presentation by a recipient HLA molecule and can theoretically occur any time after the transplant, it has been postulated that CD4 ϩ T cells responding through the indirect pathway actually play a dominant role in the development of CAN (20). Indeed, results from several laboratories have provided strong correlative evidence that indirectly primed CD4 ϩ T cells are associated with clinical/pathologic evidence of chronic allograft injury (22)(23)(24)(25)(26)(27). Alloreactive T cells also directly recognize allo-MHC molecules on the surface of donor antigen presenting cells (APC).…”

mentioning

confidence: 99%

Alloreactivity in Renal Transplant Recipients with and without Chronic Allograft Nephropathy

Poggio¹,

Clemente²,

Riley³

et al. 2004

Journal of the American Society of Nephrology

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Abstract. The pathogenesis of chronic allograft nephropathy (CAN) involves both immunologic (antigen-dependent) and nonimmunologic (antigen-independent) mechanisms. In order to provide further insight into the immunologic basis of this disease, a cross-sectional analysis of cellular and humoral immunity in human renal allograft recipients with or without deteriorating renal function and biopsy proven CAN was performed. Interferon-␥ enzyme-linked immunosorbent spot assays were used to assess cellular immunity to donor, or fully mismatched third-party stimulator cells (direct pathway), and to synthetic peptides derived from donor HLA molecules (indirect pathway). Anti-HLA antibodies were evaluated by flow cytometry using HLA-coated beads. Both the mean frequencies of donor-reactive peripheral blood lymphocytes and the number of individuals who responded to donor antigens per group were statistically higher in CAN patients versus control subjects (P Ͻ 0.02). Calculated ratios of donor/third-party enzyme-linked immunosorbent spot responses showed mean values of 2.61 Ϯ 3.0 in the CAN group, with ratios of 0.50 to 0.72 Ϯ 0.42 in control subjects (P Ͻ 0.001), confirming that direct, donor-specific cellular immunity predominated in patients with CAN.

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“…Theoretically, depletion of allogeneic APCs will prevent the response of recipient CD4 + T cells toward foreign HLA class II molecules, referred to as the direct way of allorecognition. As shown in Table 2A, the stimulation of recipient CD4 + T cells with APC‐depleted allogeneic peripheral blood mononuclear cells (PBMCs) correlated with acute rejection in two studies (44, 45), whereas other studies found no correlation between indirect allorecognition and acute allograft rejection (39, 41, 46). However, it cannot be ruled out that direct allorecognition still interferes in the immune reaction as small numbers of residual donor APCs may remain present.…”

Section: Allogeneic Cells Depleted Of Apcsmentioning

confidence: 99%

“…As chronic allograft rejection is thought to be mediated mainly by recipient T cells with indirect allospecificity, most in vitro assays aiming to detect indirect allorecognition have been performed after solid organ transplantation. As depicted in Table 2, recipient T‐cell reactivity to donor‐like or donor‐derived antigens was associated with acute as well as chronic rejection in numerous studies, except for some (38–43). However, in the following sections, it will become evident that test conditions vary considerably among studies, while often essential controls are lacking.…”

Section: In Vitro Assays To Monitor Indirect Allorecognitionmentioning

confidence: 99%

Monitoring of indirect allorecognition: wishful thinking or solid data?

et al. 2007

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Monitoring of T cells involved in the alloimmune response after transplantation requires the availability of reliable in vitro assays for the detection of T cells with both direct and indirect allospecificity. While generally accepted assays exist to measure helper and cytotoxic T cells involved in direct allorecognition, consensus about an assay for monitoring indirect T-cell allorecognition in clinical transplantation is lacking. Many studies claim a relationship between the reactivity of T cells with indirect allospecificity and graft rejection, but different protocols are used and essential controls are often lacking. In this review, the disadvantages and pitfalls of the current approaches are discussed, in some cases supported by the results of our own in vitro experiments. We conclude that an international workshop is necessary to establish and validate a uniform, robust and reliable assay for the monitoring of transplant recipients and to study the actual role of indirect allorecognition in acute and chronic rejection.

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Evidence of Indirect Allorecognition in Long-Term Human Renal Transplantation

Cited by 13 publications

References 31 publications

CD4⁺CD25⁺Foxp3⁺ Indirect Alloreactive T cells from Renal Transplant Patients Suppress Both the Direct and Indirect Pathways of Allorecognition

CD4⁺CD25⁺Foxp3⁺ Indirect Alloreactive T cells from Renal Transplant Patients Suppress Both the Direct and Indirect Pathways of Allorecognition

Alloreactivity in Renal Transplant Recipients with and without Chronic Allograft Nephropathy

Monitoring of indirect allorecognition: wishful thinking or solid data?

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Evidence of Indirect Allorecognition in Long-Term Human Renal Transplantation

Cited by 13 publications

References 31 publications

CD4+CD25+Foxp3+ Indirect Alloreactive T cells from Renal Transplant Patients Suppress Both the Direct and Indirect Pathways of Allorecognition

CD4+CD25+Foxp3+ Indirect Alloreactive T cells from Renal Transplant Patients Suppress Both the Direct and Indirect Pathways of Allorecognition

Alloreactivity in Renal Transplant Recipients with and without Chronic Allograft Nephropathy

Monitoring of indirect allorecognition: wishful thinking or solid data?

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Resources

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CD4⁺CD25⁺Foxp3⁺ Indirect Alloreactive T cells from Renal Transplant Patients Suppress Both the Direct and Indirect Pathways of Allorecognition

CD4⁺CD25⁺Foxp3⁺ Indirect Alloreactive T cells from Renal Transplant Patients Suppress Both the Direct and Indirect Pathways of Allorecognition