Are there advantages in the use of specific pathogen‐free baboons in pig organ xenotransplantation models?

Zhou, Huidong; Iwase, Hayato; Wolf, Roman F.; Ekser, Burçin; Ezzelarab, Mohamed; Hara, Hidetaka; White, Gary L.; Cooper, D. K. C.

doi:10.1111/xen.12088

Cited by 18 publications

(16 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Before transplantation, the baboon had high serum levels of anti-non-Gal IgM antibodies (similar to levels seen in baboons previously sensitized to pig antigens) and significantly higher than we have documented previously in baboons from the specific pathogen-free colony [5] (Fig. 4A).…”

Section: Immune Monitoringsupporting

confidence: 83%

Pig kidney graft survival in a baboon for 136 days: longest life‐supporting organ graft survival to date

Iwase

Liu

Wijkstrom

et al. 2015

Xenotransplantation

Self Cite

189

225

View full text Add to dashboard Cite

The longest survival of a nonhuman primate with a life-supporting kidney graft to date has been 90 days, though graft survival >30 days has been unusual. A baboon received a kidney graft from an α1,3-galactosyltransferase gene-knockout pig transgenic for two human complement- and three human coagulation- regulatory proteins (though only one was expressed in the kidney). Immunosuppressive therapy was with ATG+anti-CD20mAb (induction) and anti-CD40mAb+rapamycin+corticosteroids (maintenance). Anti-TNF-α and anti-IL-6R were administered. The baboon survived 136 days with a generally stable serum creatinine (0.6–1.6mg/dL) until terminally. No features of a consumptive coagulopathy (e.g., thrombocytopenia, decreased fibrinogen) or of a protein-losing nephropathy were observed. There was no evidence of an elicited anti-pig antibody response. Death was from septic shock (Myroides spp). Histology of a biopsy on day 103 was normal, but by day 136 the kidney showed features of glomerular enlargement, thrombi, and mesangial expansion. The combination of (i) a graft from a specific genetically-engineered pig, (ii) an effective immunosuppressive regimen, and (iii) anti-inflammatory agents prevented immune injury and a protein-losing nephropathy, and delayed coagulation dysfunction. This outcome encourages us that clinical renal xenotransplantation may become a reality.

show abstract

Section: Immune Monitoringsupporting

confidence: 83%

Pig kidney graft survival in a baboon for 136 days: longest life‐supporting organ graft survival to date

Iwase

Liu

Wijkstrom

et al. 2015

Xenotransplantation

Self Cite

189

225

View full text Add to dashboard Cite

show abstract

“…Interestingly, pre-transplant anti-non-Gal IgM levels in baboons from this study were generally higher than in a normal human serum pool (MFI = 35 AE 15, dotted box in Fig. 2A) and higher than in specific pathogen-free baboons [24,25]. In contrast, early xenografts performed with GalTKO organs employed baboons selected for low anti-non-Gal antibody levels [3].…”

Section: Discussionmentioning

confidence: 58%

Early graft failure of GalTKO pig organs in baboons is reduced by expression of a human complement pathway‐regulatory protein

Azimzadeh

Kelishadi

Ezzelarab

et al. 2015

Xenotransplantation

Self Cite

View full text Add to dashboard Cite

Background We describe the incidence of early graft failure (EGF, defined as loss of function from any cause within 3 days after transplant) in a large cohort of GalTKO pig organs transplanted into baboons in three centers, and the effect of additional expression of a human complement pathway-regulatory protein, CD46 or CD55 (GalTKO.hCPRP). Methods Baboon recipients of life-supporting GalTKO kidney (n = 7) or heterotopic heart (n = 14) grafts received either no immunosuppression (n = 4), or one of several partial or full immunosuppressive regimens (n = 17). Fourteen additional baboons received a GalTKO.hCPRP kidney (n = 5) or heart (n = 9) and similar treatment regimens. Immunologic, pathologic, and coagulation parameters were measured at frequent intervals. Results EGF of GalTKO organs occurred in 9/21 baboons (43%). hCPRP expression reduced the GalTKO EGF incidence to 7% (1/14; p<0.01 vs GalTKO alone). At 30 min, complement deposits were more intense in organs in which EGF developed (p<0.005). The intensity of peri-transplant platelet activation (as β-thromboglobulin release) correlated with EGF, as did the cumulative coagulation score (p<0.01). Conclusions We conclude that (i) the transgenic expression of a hCPRP on the vascular endothelium of a GalTKO pig reduces the incidence of EGF, and reduces complement deposition, (ii) complement deposition and platelet activation correlate with early GalTKO organ failure, and (iii) the expression of a hCPRP reduces EGF but does not prevent systemic coagulation activation. Additional strategies will be required to control coagulation activation.

show abstract

“…These SPF baboons are known to have lower levels of both anti non Gal IgG and IgM (6) (7). Four to eight week old genetically modified pigs that were alpha galactosidase transferase knockout and hCD46 transgenic (GTKO.hCD46), with or without TBM expression (Revivicor Inc., Blacksburg, VA), were used as heart donors.…”

Section: Methodsmentioning

confidence: 99%

Genetically engineered pigs and target-specific immunomodulation provide significant graft survival and hope for clinical cardiac xenotransplantation

Mohiuddin

Singh

Corcoran

et al. 2014

The Journal of Thoracic and Cardiovascular Surgery

116

115

View full text Add to dashboard Cite

Objective Cardiac transplantation, along with available mechanical alternatives, are the only possible solutions for end stage cardiac disease. Unfortunately, due to the limited supply of human organs, xenotransplantation may be the ideal method to overcome this shortage. Recently we have seen significant prolongation of heterotopic cardiac xenograft survival from three months to twelve months and beyond. Methods Hearts from genetically engineered (GE) piglets that were alpha 1–3 galactosidase transferase knockout (GTKO) and expressed the human complement regulatory gene, CD46 (hCD46)(Group A, B, C), and the human Thrombomodulin (hTBM) gene (Group D), were heterotropically transplanted in baboons treated with anti-thymocyte globulin (ATG), cobra venom factor (CVF), anti CD20 antibody, and costimulation blockade (anti CD154 antibody (clone 5C8), in group A, or anti-CD40 antibody (clone 3A8;20mg/Kg) in group B, clone 2C10R4 (25mg/Kg) in group C, or clone 2C10R4 (50mg/Kg) in group D, along with conventional non-specific immunosuppressive agents. Results Group A grafts (n=8) survived for an average of 70 days with the longest survival of 236 days. Some animals in this group (n=3) developed microvascular thrombosis due to platelet activation and consumption, which resulted in spontaneous hemorrhage. The median survival time in group B (n=3) was 21 days, group C (n=6) was 80 days, and group D (n=5) was >200days. Three grafts in group D are still contracting well, with the longest ongoing graft survival surpassing the one-year mark. Conclusion GE pig hearts (GTKOhTg.hCD46.hTBM) with modified targeted immunosuppression (anti CD40mAb) achieved long term cardiac xenograft survival. This potentially paves the way for clinical xenotransplantation if similar survival can be reproduced in an orthotopic transplantation model.

show abstract

Are there advantages in the use of specific pathogen‐free baboons in pig organ xenotransplantation models?

Cited by 18 publications

References 17 publications

Pig kidney graft survival in a baboon for 136 days: longest life‐supporting organ graft survival to date

Pig kidney graft survival in a baboon for 136 days: longest life‐supporting organ graft survival to date

Early graft failure of GalTKO pig organs in baboons is reduced by expression of a human complement pathway‐regulatory protein

Genetically engineered pigs and target-specific immunomodulation provide significant graft survival and hope for clinical cardiac xenotransplantation

Contact Info

Product

Resources

About