Chronic Rejection

Gasser, Martin; Waaga-Gasser, Ana Maria; Holthe, Joana E. Kist-van; Yuan, Xin; Lenhard, Susanne M.; Abdallah, Kald; Chandraker, Anil

doi:10.1097/01.asn.0000112022.26224.e5

Cited by 12 publications

(5 citation statements)

References 32 publications

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“…In rat experimental models, TNFa mRNA expression is upregulated in tissue samples during both acute and chronic kidney allograft rejection. 183,184 In humans, TNFa expression is also increased in renal tissue during acute rejection. [185][186][187] Plasmatic and urinary TNFa levels are also significantly elevated, 188,189 as well as circulating soluble TNFR1 and TNFR2.…”

Section: Kidney Allograft Rejectionmentioning

confidence: 99%

Immunoregulatory role of TNFα in inflammatory kidney diseases

Ernandez

Mayadas

2009

Kidney International

137

114

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Tumor necrosis factor alpha (TNFalpha), a pleiotropic cytokine, plays important inflammatory roles in renal diseases such as lupus nephritis, anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis and renal allograft rejection. However, TNFalpha also plays critical immunoregulatory roles that are required to maintain immune homeostasis. These complex biological functions of TNFalpha are orchestrated by its two receptors, TNFR1 and TNFR2. For example, TNFR2 promotes leukocyte infiltration and tissue injury in an animal model of immune complex-mediated glomerulonephritis. On the other hand, TNFR1 plays an immunoregulatory function in a murine lupus model with a deficiency in this receptor that leads to more severe autoimmune symptoms. In humans, proinflammatory and immunoregulatory roles for TNFalpha are strikingly illustrated in patients on anti-TNFalpha medications: These treatments are greatly beneficial in certain inflammatory diseases such as rheumatoid arthritis but, on the other hand, are also associated with the induction of autoimmune lupus-like syndromes and enhanced autoimmunity in multiple sclerosis patients. The indication for anti-TNFalpha treatments in renal inflammatory diseases is still under discussion. Ongoing clinical trials may help to clarify the potential benefit of such treatments in lupus nephritis and ANCA-associated glomerulonephritis. Overall, the complex biology of TNFalpha is not fully understood. A greater understanding of the function of its receptors may provide a framework to understand its contrasting proinflammatory and immunoregulatory functions. This may lead the development of new, more specific anti-inflammatory drugs.

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Section: Kidney Allograft Rejectionmentioning

confidence: 99%

Immunoregulatory role of TNFα in inflammatory kidney diseases

Ernandez

Mayadas

2009

Kidney International

137

114

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“…Urinary protein excretion is a sensitive measure of progression of chronic allograft dysfunction in this model. 20 Isograft recipients had baseline urinary protein excretion of Ͻ20 mg/24 h throughout the follow-up period (Figure 2A). Control rats treated with CsA developed progressive proteinuria indicative of chronic allograft dysfunction.…”

Section: Graft Survival and Functionmentioning

confidence: 99%

Regulatory Allospecific T Cell Clones Abrogate Chronic Allograft Rejection

Waaga-Gasser

Grimm²,

Lutz³

et al. 2009

Journal of the American Society of Nephrology

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True alloantigen-specific tolerance is the ultimate goal of solid organ transplantation, eliminating the need for long-term immunosuppression. Recent evidence suggests that Th1-derived cytokines are associated with rejection and Th2-derived cytokines with long-term allograft survival, but the roles of these subsets in rejection and tolerance are incompletely understood. Here, we analyzed the functional and regulatory capacities of T cell clones derived from tolerant and rejecting rats (Wistar rat donors, Lewis rat recipients). We generated and subcloned T cell lines from lymphocytes derived from either acutely rejecting grafts or from the grafts of CTLA4-Ig-treated tolerant rats. Pretransplantation adoptive transfer of T cell clones generated from rejected grafts (Th1 clones) accelerated acute rejection or promoted development of chronic rejection, whereas transfer of T cell clones generated from tolerized grafts (Th2 clones) protected rats from acute rejection and progressive organ dysfunction. When Th1 and Th2 clones were injected simultaneously, Th2 clones specifically regulated activation of Th1 clones. Rats that received injections of Th2 clones accepted long-term donor-specific skin grafts but acutely rejected third-party skin grafts. Tolerant rats treated with Th2 clones demonstrated an increased number of regulatory CD4+CD25+Foxp3+ cells and strong mononuclear cell staining for IL-10 but negligible IFN-gamma, IL-17, and IL-23 compared with untreated rats or those treated with Th1 clones. In summary, these results demonstrate the regulatory functions of Th2 cells in a clinically relevant allogeneic transplant model and provide new insight into the functional role of Th2 cells in preventing the process of chronic rejection.

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“…After transplantation and following direct or indirect antigen presentation, recipient CD4+ T cells become activated, differentiate into T helper (Th)‐type 1 and 2 cells, and secrete specific cytokines which further modulate the activation of macrophages, cytotoxic CD8+ T cells and B cells. Th1 cytokines (such as IL‐2, TNF‐α, IFN‐γ) are thought to be involved in the pathogenesis of renal transplant rejection, whereas Th2 cytokines (such as IL‐4, IL‐10, IL‐13) may ameliorate it, though studies attempting to correlate expression of various cytokines with transplantation outcome provided partially discrepant results 5–9.…”

Section: Introductionmentioning

confidence: 99%