A model of acute renal allograft rejection in outbred Yorkshire piglets

Lassiter, Randi; Wang, Youli; Fang, Xuexiu; Winn, Matt; Ghaffari, A.; Ho, Chak-Sum; Helman, Sandra W.; Jajosky, Ryan Philip; Kleven, Daniel; Nahman, N. S.; Merchen, Todd

doi:10.1016/j.trim.2017.05.001

Cited by 5 publications

(13 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In previous studies, we reported our experience with a porcine model of allogeneic kidney transplantation 23. The current work extends those observations and investigates the regulation of IDO and its role in acute rejection.…”

Section: Introductionsupporting

confidence: 54%

“…In brief, one pair of pigs was operated simultaneously, the left kidneys exchanged (allotransplants) or retransplanted (autotransplants). All transplants were ex vivo perfused at 4°C and orthotopically transplanted, followed by right nephrectomy (control tissue) and closure 23. No immunosuppression was used.…”

Section: Methodsmentioning

confidence: 99%

“…Animals were sacrificed under general anesthesia and at the conclusion of the harvest. When indicated, swine leukocyte antigen (SLA) genotyping was performed, and histologic scoring according to Banff criteria was conducted as we described 23. Tissues from control right kidneys, autotransplants, and allotransplants were probed for IDO and cytokine gene and protein expression, and IDO enzymatic activity.…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Regulation of indoleamine 2,3 dioxygenase and its role in a porcine model of acute kidney allograft rejection

Wang

Merchen

Fang

et al. 2018

Journal of Investigative Medicine

Self Cite

View full text Add to dashboard Cite

In kidney transplantation acute allograft rejection is the most common cause of late allograft loss. Changes in indoleamine 2,3 dioxygenase (IDO) activity, which catabolizes the degradation of tryptophan to kynurenine, may predict rejection. However, exogenous IDO is immunosuppressive in rodent kidney transplantation. Thus, the increase in IDO activity observed in acute allograft rejection is insufficient to prevent rejection. To address this question, we assessed the regulation of IDO and its role in acute rejection in a porcine model of kidney transplant. In tissue samples from rejecting kidney allografts, we showed a 13-fold increase in IDO gene transcription and 20-fold increase in IDO enzyme activity when compared with autotransplanted kidneys. Allografts also demonstrated an over fourfold increase in tissue interferon (IFN)-γ, with marked increases in tumor necrosis factor (TNF)-α, TNF-β and interleukin 1β. Gene transcription and protein levels of kynurenine 3-monooxygenase (KMO) were decreased. KMO generates the immunosuppressive kynurenine, 3-hydroxykynurenine. The results of these studies demonstrate a clear association between rejection and increased allograft IDO expression, likely driven in part by IFN-γ and facilitated by other cytokines of the allogeneic response. Moreover, the loss of downstream enzymatic activity in the IDO metabolic pathway may suggest novel mechanisms for the perpetuation of rejection.

show abstract

Section: Introductionsupporting

confidence: 54%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Regulation of indoleamine 2,3 dioxygenase and its role in a porcine model of acute kidney allograft rejection

Wang

Merchen

Fang

et al. 2018

Journal of Investigative Medicine

Self Cite

View full text Add to dashboard Cite

show abstract

“…The recognition of SLA alleles as transplant determinants on allograft survival was first documented 40 years ago in the NIH/MGH miniature swine transplant model (110), a model that has resulted in the publication of numerous cutting-edge transplantation experiments worldwide (111)(112)(113). Without immunosuppressive conditioning, pigs receiving a kidney allograft with at least one SLA haplotype mismatch had moderate to severe cellular rejection, whereas a "perfect" SLAmatched kidney displayed normal renal allograft histology and serum creatinine with no evidence of rejection (106). It should be noted that the pig that received a blood group-incompatible kidney (A to O) experienced hyperacute rejection (114).…”

Section: Solid Organ Transplantationmentioning

confidence: 99%

Importance of the Major Histocompatibility Complex (Swine Leukocyte Antigen) in Swine Health and Biomedical Research

Hammer

Andõ

et al. 2020

Annu. Rev. Anim. Biosci.

Self Cite

View full text Add to dashboard Cite

In pigs, the major histocompatibility complex (MHC), or swine leukocyte antigen (SLA) complex, maps to Sus scrofa chromosome 7. It consists of three regions, the class I and class III regions mapping to 7p1.1 and the class II region mapping to 7q1.1. The swine MHC is divided by the centromere, which is unique among mammals studied to date. The SLA complexspans between 2.4 and 2.7 Mb, depending on haplotype, and encodes approximately 150 loci, with at least 120 genes predicted to be functional. Here we update the whole SLA complex based on the Sscrofa11.1 build and annotate the organization for all recognized SLA genes and their allelic sequences. We present SLA nomenclature and typing methods and discuss the expression of SLA proteins, as well as their role in antigen presentation and immune, disease, and vaccine responses. Finally, we explore the role of SLA genes in transplantation and xenotransplantation and their importance in swine biomedical models.

show abstract

“…Five of the twenty pigs (two of which were twins) experienced allograft rejection rated IIA on the Banff scale, while six pigs experienced allograft rejection below IIA on the Banff scale. Pigs with allograft rejection rated IIA and lower had normal physiological parameters (40,50). Nine of the twenty pigs had allograft rejection rated above Banff scale IIA and abnormal physiological function (Figure 1A).…”

Section: Pathology and Gene Expression Of Grafts In Pig Kidney Transplantationmentioning

confidence: 99%

Protective Role of Kynurenine 3-Monooxygenase in Allograft Rejection and Tubular Injury in Kidney Transplantation

et al. 2021

Self Cite

View full text Add to dashboard Cite

Renal tubular epithelial cells (TECs) are the primary targets of ischemia–reperfusion injury (IRI) and rejection by the recipient’s immune response in kidney transplantation (KTx). However, the molecular mechanism of rejection and IRI remains to be identified. Our previous study demonstrated that kynurenine 3-monooxygenase (KMO) and kynureninase were reduced in ischemia–reperfusion procedure and further decreased in rejection allografts among mismatched pig KTx. Herein, we reveal that TEC injury in acutely rejection allografts is associated with alterations of Bcl2 family proteins, reduction of tight junction protein 1 (TJP1), and TEC-specific KMO. Three cytokines, IFNγ, TNFα, and IL1β, reported in our previous investigation were identified as triggers of TEC injury by altering the expression of Bcl2, BID, and TJP1. Allograft rejection and TEC injury were always associated with a dramatic reduction of KMO. 3HK and 3HAA, as direct and downstream products of KMO, effectively protected TEC from injury via increasing expression of Bcl-xL and TJP1. Both 3HK and 3HAA further prevented allograft rejection by inhibiting T cell proliferation and up-regulating aryl hydrocarbon receptor expression. Pig KTx with the administration of DNA nanoparticles (DNP) that induce expression of indoleamine 2,3-dioxygenase (IDO) and KMO to increase 3HK/3HAA showed an improvement of allograft rejection as well as murine skin transplant in IDO knockout mice with the injection of 3HK indicated a dramatic reduction of allograft rejection. Taken together, our data provide strong evidence that reduction of KMO in the graft is a key mediator of allograft rejection and loss. KMO can effectively improve allograft outcome by attenuating allograft rejection and maintaining graft barrier function.

show abstract

A model of acute renal allograft rejection in outbred Yorkshire piglets

Cited by 5 publications

References 27 publications

Regulation of indoleamine 2,3 dioxygenase and its role in a porcine model of acute kidney allograft rejection

Regulation of indoleamine 2,3 dioxygenase and its role in a porcine model of acute kidney allograft rejection

Importance of the Major Histocompatibility Complex (Swine Leukocyte Antigen) in Swine Health and Biomedical Research

Protective Role of Kynurenine 3-Monooxygenase in Allograft Rejection and Tubular Injury in Kidney Transplantation

Contact Info

Product

Resources

About