Humoral Reactivity of Renal Transplant-Waitlisted Patients to Cells From GGTA1/CMAH/B4GalNT2, and SLA Class I Knockout Pigs

Martens, Gregory R.; Reyes, Luz M.; Butler, James; Ladowski, Joseph M.; Estrada, José L.; Sidner, Richard A.; Eckhoff, Devin E.; Tector, Matt; Tector, A. Joseph

doi:10.1097/tp.0000000000001646

Cited by 191 publications

(224 citation statements)

References 26 publications

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“…In contrast lack of class II expression on pig stimulator cells reduced NHP CD4 + T cell proliferation to the same level as those without xenogeneic stimulation ( Figure 6F). [60][61][62] In conclusion, these results describe the longest-reported lifesustaining xenotransplants to date. One possible explanation for shorter graft survival times in pig-to-baboon models using depletion therapies with anti-thymocyte globulin versus our model is our use of a pretransplant antibody screen that we have previously detailed.…”

Section: F I G U R E 3 Cd4 + T Cells Proliferatesupporting

confidence: 60%

Long-term survival of pig-to-rhesus macaque renal xenografts is dependent on CD4 T cell depletion

Kim

Mathews

Breeden

et al. 2019

American Journal of Transplantation

165

140

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The shortage of available organs remains the greatest barrier to expanding access to transplant. Despite advances in genetic editing and immunosuppression, survival in experimental models of kidney xenotransplant has generally been limited to <100 days. We found that pretransplant selection of recipients with low titers of anti-pig antibodies significantly improved survival in a pig-to-rhesus macaque kidney transplant model (6 days vs median survival time 235 days). Immunosuppression included transient pan-T cell depletion and an anti-CD154-based maintenance regimen. Selective depletion of CD4 + T cells but not CD8 + T cells resulted in long-term survival (median survival time >400 days vs 6 days). These studies suggested that CD4 + T cells may have a more prominent role in xenograft rejection compared with CD8 + T cells. Although animals that received selective depletion of CD8 + T cells showed signs of early cellular rejection (marked CD4 + infiltrates), animals receiving selective CD4 + depletion exhibited normal biopsy results until late, when signs of chronic antibody rejection were present. In vitro study results suggested that rhesus CD4 + T cells required the presence of SLA class II to mount an effective proliferative response. The combination of low pretransplant anti-pig antibody and CD4 depletion resulted in consistent, long-term xenograft survival. K E Y W O R D Sanimal models: nonhuman primate, basic (laboratory) research/science, costimulation, immunosuppressant -fusion proteins and monoclonal antibodies: costimulation molecule specific, immunosuppression/immune modulation, kidney transplantation/nephrology, translational research/science, xenoantibody, xenoantigen, xenotransplantation

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Section: F I G U R E 3 Cd4 + T Cells Proliferatesupporting

confidence: 60%

Long-term survival of pig-to-rhesus macaque renal xenografts is dependent on CD4 T cell depletion

Kim

Mathews

Breeden

et al. 2019

American Journal of Transplantation

165

140

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“…As in alloreactivity, MHC molecules (swine leukocyte antigen [SLA]) of the porcine donor trigger the recipient's T cell responses after xenotransplantation . Furthermore, porcine SLA molecules are targets of cross‐reacting anti‐HLA antibodies . Because of the possibility to genetically engineer the porcine donor, the generation of immune protected organs and tissues via the elimination of MHC molecules might be particularly beneficial in xenotransplantation rather than in allotransplantation.…”

Section: Introductionmentioning

confidence: 99%

Triple (GGTA1, CMAH, B2M) modified pigs expressing an SLA class Ilow phenotype—Effects on immune status and susceptibility to human immune responses

Hein

Sake

Pokoyski

et al. 2020

American Journal of Transplantation

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Porcine xenografts lacking swine leukocyte antigen (SLA) class I are thought to be protected from human T cell responses. We have previously shown that SLA class I deficiency can be achieved in pigs by CRISPR/Cas9‐mediated deletion of β2‐microglobulin (B2M). Here, we characterized another line of genetically modified pigs in which targeting of the B2M locus did not result in complete absence of B2M and SLA class I but rather in significantly reduced expression levels of both molecules. Residual SLA class I was functionally inert, because no proper differentiation of the CD8+ T cell subset was observed in B2Mlow pigs. Cells from B2Mlow pigs were less capable in triggering proliferation of human peripheral blood mononuclear cells in vitro, which was mainly due to the nonresponsiveness of CD8+ T cells. Nevertheless, cytotoxic effector cells developing from unaffected cell populations (eg, CD4+ T cells, natural killer cells) lysed targets from both SLA class I+ wildtype and SLA class Ilow pigs with similar efficiency. These data indicate that the absence of SLA class I is an effective approach to prevent the activation of human CD8+ T cells during the induction phase of an anti‐xenograft response. However, cytotoxic activity of cells during the effector phase cannot be controlled by this approach.

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“…Pigs were produced with inactivated GGTA1, GGTA1/CMAH, and GGTA1/CMAH/β4GalNT2 (TKO) genes . Of all pigs tested, PBMC from these TKO pigs bound the least human IgG and IgM . 31% of 820 waitlisted renal transplant patients exhibited both IgM and IgG binding levels to the TKO PBMC that closely approximated or matched negative control levels .…”

Section: Sequentially Disrupting Pig Xenoantigens Minimizes Human Antmentioning

confidence: 99%

The desirable donor pig to eliminate all xenoreactive antigens

Ladowski

Martens

Estrada

et al. 2019

Xenotransplantation

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The humoral barrier has been the limiting factor in moving xenotransplantation towards the clinic. Improvements in somatic cell nuclear transfer and genome editing, particularly CRISPR‐Cas9, have made it possible to create pigs with multiple glycan xenoantigen deletions for the purposes of reducing xenoreactive antibody binding to the xenografted organ. Recent studies have also considered the aetiology and existence of antibodies directed at the swine leucocyte antigen (SLA) complex, and potential genetic engineering strategies to avoid these antibodies. Evaluation of xenoreactive antibody binding is very important for the advancement of xenotransplantation, because if patients do not have any detectable xenoreactive antibody, then it is reasonable to expect that cellular rejection and not antibody‐mediated rejection (AMR) will be the next hurdle to clinical application.

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Humoral Reactivity of Renal Transplant-Waitlisted Patients to Cells From GGTA1/CMAH/B4GalNT2, and SLA Class I Knockout Pigs

Abstract: Many waitlisted patients have minimal xenoreactive antibody binding to the triple KO pig, but some HLA antibodies in sensitized patients cross-react with class I SLA. SLA class I is a target for genome editing in xenotransplantation.

Cited by 191 publications

References 26 publications

Long-term survival of pig-to-rhesus macaque renal xenografts is dependent on CD4 T cell depletion

Long-term survival of pig-to-rhesus macaque renal xenografts is dependent on CD4 T cell depletion

Triple (GGTA1, CMAH, B2M) modified pigs expressing an SLA class Ilow phenotype—Effects on immune status and susceptibility to human immune responses

The desirable donor pig to eliminate all xenoreactive antigens

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