Inflammatory triggers of acute rejection of organ allografts

Mori, Daniel N.; Kreisel, Daniel; Fullerton, James N.; Gilroy, Derek W.; Goldstein, Daniel R.

doi:10.1111/imr.12146

Cited by 111 publications

(88 citation statements)

References 118 publications

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“…23,37,53 We suggest that suppressing the inflammatory response may well facilitate the role of the immunosuppressive therapy and reduce the risk of both rejection and coagulation dysfunction. [54][55][56] We have data suggesting that the cytokine, interleukin-6 (IL-6), is playing a role and that IL-6R blockade reduces this response. 23 IL-6R blockade does not have an inhibitory effect on platelet aggregation in vitro (H. Iwase unpublished data).…”

mentioning

confidence: 99%

Immunological and physiological observations in baboons with life‐supporting genetically engineered pig kidney grafts

Iwase

Hara

Ezzelarab

et al. 2017

Xenotransplantation

184

287

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Background Genetically-engineered pigs could provide a source of kidneys for clinical transplantation. The two longest kidney graft survivals reported to date have been 136 days and 310 days, but graft survival >30 days has been unusual until recently. Methods Donor pigs (n=4) were on an α1,3-galactosyltransferase gene-knockout (GTKO)/human complement-regulatory protein (CD46) background (GTKO/CD46). In addition, the pigs were transgenic for at least one human coagulation-regulatory protein. Two baboons received a kidney from a 6-gene pig (Group A) and two from a 3-gene pig (Group B). Immunosuppressive therapy was identical in all 4 cases, and consisted of anti-thymoglobulin (ATG) + anti-CD20mAb (induction) and anti-CD40mAb + rapamycin + corticosteroids (maintenance). Anti-TNF-α and anti-IL-6R mAbs were administered to reduce the inflammatory response. Baboons were followed by clinical/laboratory monitoring of immune/coagulation/inflammatory/physiological parameters. At biopsy or euthanasia, the grafts were examined by microscopy. Results The two Group A baboons remained healthy with normal renal function >7 and >8 months, respectively, but then developed infectious complications. However, no features of a consumptive coagulopathy, e.g., thrombocytopenia, reduction of fibrinogen, or of a protein-losing nephropathy were observed. There was no evidence of an elicited anti-pig antibody response, and histology of biopsies taken at approximately 4, 6, and 7 months and at necropsy showed no significant abnormalities. In contrast, both Group B baboons developed features of a consumptive coagulopathy and required euthanasia on day 12. Conclusions The combination of (i) a graft from a specific 6-gene genetically-modified pig, (ii) an effective immunosuppressive regimen, and (iii) anti-inflammatory therapy prevented immune injury, a protein-losing nephropathy, and coagulation dysfunction for >7 months. Although the number of experiments is very limited, our impression is that expression of human endothelial protein C receptor (+/− CD55) in the graft is important if coagulation dysregulation is to be avoided.

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mentioning

confidence: 99%

Immunological and physiological observations in baboons with life‐supporting genetically engineered pig kidney grafts

Iwase

Hara

Ezzelarab

et al. 2017

Xenotransplantation

184

287

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“…34 Our data showed that the phosphorylation of NFκB-p65 was significantly increased in DCD allografts with low-dose tacrolimus compared to the CIT-only control. 34 Our data showed that the phosphorylation of NFκB-p65 was significantly increased in DCD allografts with low-dose tacrolimus compared to the CIT-only control.…”

Section: High Immunosuppression Reduced Apoptosis In the Renal Allomentioning

confidence: 51%

“…It has been shown that the inflammatory cytokines produced in IRI may enhance the adaptive immune response to the allograft after transplantation. 34,35 Therefore, we investigated the activation of Our data showed that the phosphorylation of NFκB-p65 was significantly increased in DCD allografts with low-dose tacrolimus compared to the CIT-only control. Phosphorylated NFκB-p65 has been associated with the inflammatory response.…”

Section: Discussionmentioning

confidence: 99%

Enhanced immunosuppression improves early allograft function in a porcine kidney transplant model of donation after circulatory death

Garcia‐Aroz

Banan

et al. 2019

American Journal of Transplantation

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It remains controversial whether renal allografts from donation after circulatory death (DCD) have a higher risk of acute rejection (AR). In the porcine large animal kidney transplant model, we investigated the AR and function of DCD renal allografts compared to the non-DCD renal allografts and the effects of increased immunosuppression. We found that the AR was significantly increased along with elevated MHC-I expression in the DCD transplants receiving low-dose immunosuppression; however, AR and renal function were significantly improved when given high-dose immunosuppressive therapy postoperatively. Also, high-dose immunosuppression remarkably decreased the mRNA levels of ifn-g, il-6, tgf-b, il-4, and tnf-a in the allograft at day 5 and decreased serum cytokines levels of IFN-g and IL-17 at day 4 and day 5 after operation. Furthermore, Western blot analysis showed that higher immunosuppression decreased phosphorylation of signal transducer and activator of transcription 3 and nuclear factor kappa-light-chain-enhancer of activated B cells-p65, increased phosphorylation of extracellular-signal-regulated kinase, and reduced the expression of Bcl-2-associated X protein and caspase-3 in the renal allografts. These results suggest that the DCD renal allograft seems to be more vulnerable to AR; enhanced immunosuppression reduces DCD-associated AR and improves early allograft function in a preclinical large animal model.

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“…Pro-inflammatory cytokines are assumed to be present at time 0 since transplantation is associated with surgical trauma and exposure to bacterial and viral agents. Additionally, during the procedure, the reconnection to the recipient circulation initiates the process of ischemia/reperfusion injury, causing rapid accumulation of inflammatory mediators (31, 42, 43). Although there is a general agreement on the presence of inflammatory elements at time 0, the overall amount is not known and, thus, an arbitrary value is chosen here.…”

Section: Methodsmentioning

confidence: 99%

Combining Theoretical and Experimental Techniques to Study Murine Heart Transplant Rejection

Arciero

Maturo

Arun³

et al. 2016

Front. Immunol.

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The quality of life of organ transplant recipients is compromised by complications associated with life-long immunosuppression, such as hypertension, diabetes, opportunistic infections, and cancer. Moreover, the absence of established tolerance to the transplanted tissues causes limited long-term graft survival rates. Thus, there is a great medical need to understand the complex immune system interactions that lead to transplant rejection so that novel and effective strategies of intervention that redirect the system toward transplant acceptance (while preserving overall immune competence) can be identified. This study implements a systems biology approach in which an experimentally based mathematical model is used to predict how alterations in the immune response influence the rejection of mouse heart transplants. Five stages of conventional mouse heart transplantation are modeled using a system of 13 ordinary differential equations that tracks populations of both innate and adaptive immunity as well as proxies for pro- and anti-inflammatory factors within the graft and a representative draining lymph node. The model correctly reproduces known experimental outcomes, such as indefinite survival of the graft in the absence of CD4+ T cells and quick rejection in the absence of CD8+ T cells. The model predicts that decreasing the translocation rate of effector cells from the lymph node to the graft delays transplant rejection. Increasing the starting number of quiescent regulatory T cells in the model yields a significant but somewhat limited protective effect on graft survival. Surprisingly, the model shows that a delayed appearance of alloreactive T cells has an impact on graft survival that does not correlate linearly with the time delay. This computational model represents one of the first comprehensive approaches toward simulating the many interacting components of the immune system. Despite some limitations, the model provides important suggestions of experimental investigations that could improve the understanding of rejection. Overall, the systems biology approach used here is a first step in predicting treatments and interventions that can induce transplant tolerance while preserving the capacity of the immune system to protect against legitimate pathogens.

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Inflammatory triggers of acute rejection of organ allografts

Cited by 111 publications

References 118 publications

Immunological and physiological observations in baboons with life‐supporting genetically engineered pig kidney grafts

Immunological and physiological observations in baboons with life‐supporting genetically engineered pig kidney grafts

Enhanced immunosuppression improves early allograft function in a porcine kidney transplant model of donation after circulatory death

Combining Theoretical and Experimental Techniques to Study Murine Heart Transplant Rejection

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