Immunological Challenges and Therapies in Xenotransplantation

Vadori, Marta

doi:10.1101/cshperspect.a015578

Cited by 19 publications

(22 citation statements)

References 163 publications

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“…However, there are parts of this puzzle that still need to be solved (10, 11). Some of the major obstacles, after overcoming the Gal antibody barrier, include the presence of preformed and elicited non Gal antibodies against multiple antigens (12), consumptive coagulopathy (CC) caused by rapid depletion of platelets (13), and TM due to an induced hypercoagulable state (14).…”

Section: Discussionmentioning

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

111

112

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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.

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Section: Discussionmentioning

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

111

112

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“…Thus, they are considered as important laboratory animal models for biomedical research, especially for tissue engineering and human organ transplantation involving xenograft procedures (19). SCID pigs can be potentially important research tools to facilitate long-term follow-up studies of immune responses, xenotransplantation, stem cells, and cancer over clinically relevant time frames.…”

Section: R Ag1/2 Genes Encode the Enzymes That Catalyze The V(d)j Recmentioning

confidence: 99%

RAG1/2 Knockout Pigs with Severe Combined Immunodeficiency

Huang

Guo

Fan

et al. 2014

The Journal of Immunology

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Pigs share many physiological, biochemical, and anatomical similarities with humans and have emerged as valuable large animal models for biomedical research. Considering the advantages in immune system resemblance, suitable size, and longevity for clinical practical and monitoring purpose, SCID pigs bearing dysfunctional RAG could serve as important experimental tools for regenerative medicine, allograft and xenograft transplantation, and reconstitution experiments related to the immune system. In this study, we report the generation and phenotypic characterization of RAG1 and RAG2 knockout pigs using transcription activator-like effector nucleases. Porcine fetal fibroblasts were genetically engineered using transcription activator-like effector nucleases and then used to provide donor nuclei for somatic cell nuclear transfer. We obtained 27 live cloned piglets; among these piglets, 9 were targeted with biallelic mutations in RAG1, 3 were targeted with biallelic mutations in RAG2, and 10 were targeted with a monoallelic mutation in RAG2. Piglets with biallelic mutations in either RAG1 or RAG2 exhibited hypoplasia of immune organs, failed to perform V(D)J rearrangement, and lost mature B and T cells. These immunodeficient RAG1/2 knockout pigs are promising tools for biomedical and translational research.

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“…Species‐specific molecules in xenografts are recognized as immunogenic non‐self and elicit an immune response to eliminate these targets . Clinically used BHV are made of animal‐derived cardiac tissues that are processed to reduce immunogenicity, but are nevertheless relatively short‐lived .…”

Section: Discussionmentioning

confidence: 99%

Characterization of immunogenic Neu5Gc in bioprosthetic heart valves

Reuven

Ben-Arye

Marshanski

et al. 2016

Xenotransplantation

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Background The two common sialic acid (Sia) in mammals are N-Acetylneuraminic acid (Neu5Ac) and its hydroxylated form N-Glycolylneuraminic acid (Neu5Gc). Unlike most mammals, humans cannot synthesize Neu5Gc that is considered foreign and recognized by circulating antibodies. Thus, Neu5Gc is a potential xenogenic carbohydrate antigen in bioprosthetic heart valves (BHV) that tend to deteriorate in time within human patients. Methods We investigated Neu5Gc expression in non-engineered animal-derived cardiac tissues and in clinically used commercial BHV, and evaluated Neu5Gc immunogenicity on BHV through recognition by human anti-Neu5Gc IgG. Results Neu5Gc was detected by immunohistochemistry in porcine aortic valves and in porcine and bovine pericardium. Qualitative analysis of Sia-linkages revealed Siaα2–3>Siaα2–6 on porcine/bovine pericardium while the opposite in porcine aortic/pulmonary valve cusps. Similarly, six commercial BHV containing either porcine aortic valve or porcine/bovine/equine pericardium revealed Siaα2–3>Siaα2–6 expression. Quantitative analysis of Sia by HPLC showed porcine/bovine pericardium express four-fold higher Neu5Gc levels compared to the porcine aortic/pulmonary valves, with Neu5Ac at six-fold over Neu5Gc. Likewise, Neu5Gc was expressed on commercial BHV (186.3±16.9 pmol Sia/μg protein), with Neu5Ac at eight-fold over Neu5Gc. Affinity-purified human anti-Neu5Gc IgG showing high specificity towards Neu5Gc-glycans (with no binding to Neu5Ac-glycans) on a glycan microarray, strongly bound to all tested commercial BHV, demonstrating Neu5Gc immune recognition in cardiac xenografts. Conclusions We conclusively demonstrated Neu5Gc expression in native cardiac tissues, as well as in six commercial BHV. These Neu5Gc xeno-antigens were recognized by human anti-Neu5Gc IgG, supporting their immunogenicity. Altogether, these findings suggest BHV-Neu5Gc/anti-Neu5Gc may play a role in valve deterioration warranting further investigation.

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Immunological Challenges and Therapies in Xenotransplantation

Cited by 19 publications

References 163 publications

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

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

RAG1/2 Knockout Pigs with Severe Combined Immunodeficiency

Characterization of immunogenic Neu5Gc in bioprosthetic heart valves

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