Profound thrombocytopenia associated with administration of multiple anti‐inflammatory agents in baboons

Bikhet, Mohamed H; Hansen‐Estruch, Christophe; Javed, Mariyam; Collins, Dalis E; Foote, Jeremy B.; Ayares, David; Hara, Hidetaka; Cooper, David K. C.

doi:10.1002/iid3.588

Cited by 3 publications

(3 citation statements)

References 15 publications

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“…APTT showed an increasing trend in the late transplantation period, indicating that hTBM and hCD39 overexpression effectively controlled coagulation. However, near the end of the experiment, the number of platelets dropped sharply, which may be related to the use of anti-inflammatory drugs (Bikhet et al, 2022).…”

Section: Discussionmentioning

confidence: 96%

Production and functional verification of 8-gene (GGTA1, CMAH, β4GalNT2, hCD46, hCD55, hCD59, hTBM, hCD39)-edited donor pigs for xenotransplantation

Wang,

Xu,

Liu

et al. 2024

Preprint

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Gene-edited pig-to-human xenotransplantation continues to make breakthroughs and is expected to enter clinic to solve the global shortage of donor organs. However, which gene combination is suitable for which organ transplantation remains unclear. In this study, we utilized CRISPR/Cas9 gene editing technology, PiggyBac transposon system and somatic cell cloning to construct GTKO/CMAHKO/β4GalNT2KO/hCD46/hCD55/hCD59 /hCD39/hTBM 8 gene-edited cloned (GEC) donor pigs, and performed pig to non-human primate (NHP) transplantation to evaluate the effectiveness of these GEC pigs. The multiple vectors were co-transfected into fetal fibroblasts of Diannan miniature pig with O blood type, and 25 colonies were screened out, and one of them carried GGTA1, CMAH and β4GalNT2 biallelic knockout and integration of hCD46, hCD55, hCD59, hTBM and hCD39 genes, which was used as a donor cell for cloning, and a 33-day-old viable fetus was obtained. The fetus was identified and confirmed for normal karyotype and the absence of three xenogeneic antigens α-Gal, Neu5Gc and Sda, and expression of hCD46, hCD55, hCD59, hTBM and hCD39 genes, then the recloning was carried out and 28 cloned piglets were obtained by natural delivery. Molecular identification at DNA, mRNA and protein levels showed that 8 gene editing (GE) was successful in these GEC piglets. Moreover, antigen-antibody binding assay and complement-dependent cytotoxicity assay demonstrated that 8GE effectively reduced the immune incompatibility and kidney xenograft survived up to 15 and 17 days into two NHPs, respectively. During this period, the recipient serum antibodies IgA and IgM, complements C3 and C4, coagulation indicators PT, APTT, TT and FIB, as well as most electrolytes and liver function indicators remained relatively stable. The 24-hour urine output and serum creatinine remained normal at a period of post-transplantation. These results indicated that the 8GEC pigs effectively alleviated immune rejection and exerted life-supporting kidney function in the recipient.

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Section: Discussionmentioning

confidence: 96%

Production and functional verification of 8-gene (GGTA1, CMAH, β4GalNT2, hCD46, hCD55, hCD59, hTBM, hCD39)-edited donor pigs for xenotransplantation

Wang,

Xu,

Liu

et al. 2024

Preprint

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“…288 When siltuximab and tocilizumab were administered together, a fatal thrombocytopenia developed. 289…”

Section: Anti-il-6r Mabsmentioning

confidence: 99%

“…As IL‐6/IL‐6R signaling enhances the generation of megakaryocytes in the bone marrow and promotes thrombopoiesis, blocking of either may result in thrombocytopenia 288 . When siltuximab and tocilizumab were administered together, a fatal thrombocytopenia developed 289 …”

Section: Prevention or Reversal Of Acute Amrmentioning

confidence: 99%

Antibody‐mediated rejection in xenotransplantation: Can it be prevented or reversed?

Habibabady,

McGrath,

Kinoshita

et al. 2023

Xenotransplantation

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Antibody‐mediated rejection (AMR) is the commonest cause of failure of a pig graft after transplantation into an immunosuppressed nonhuman primate (NHP). The incidence of AMR compared to acute cellular rejection is much higher in xenotransplantation (46% vs. 7%) than in allotransplantation (3% vs. 63%) in NHPs. Although AMR in an allograft can often be reversed, to our knowledge there is no report of its successful reversal in a pig xenograft. As there is less experience in preventing or reversing AMR in models of xenotransplantation, the results of studies in patients with allografts provide more information. These include (i) depletion or neutralization of serum anti‐donor antibodies, (ii) inhibition of complement activation, (iii) therapies targeting B or plasma cells, and (iv) anti‐inflammatory therapy. Depletion or neutralization of anti‐pig antibody, for example, by plasmapheresis, is effective in depleting antibodies, but they recover within days. IgG‐degrading enzymes do not deplete IgM. Despite the expression of human complement‐regulatory proteins on the pig graft, inhibition of systemic complement activation may be necessary, particularly if AMR is to be reversed. Potential therapies include (i) inhibition of complement activation (e.g., by IVIg, C1 INH, or an anti‐C5 antibody), but some complement inhibitors are not effective in NHPs, for example, eculizumab. Possible B cell‐targeted therapies include (i) B cell depletion, (ii) plasma cell depletion, (iii) modulation of B cell activation, and (iv) enhancing the generation of regulatory B and/or T cells. Among anti‐inflammatory agents, anti‐IL6R mAb and TNF blockers are increasingly being tested in xenotransplantation models, but with no definitive evidence that they reverse AMR. Increasing attention should be directed toward testing combinations of the above therapies. We suggest that treatment with a systemic complement inhibitor is likely to be most effective, possibly combined with anti‐inflammatory agents (if these are not already being administered). Ultimately, it may require further genetic engineering of the organ‐source pig to resolve the problem entirely, for example, knockout or knockdown of SLA, and/or expression of PD‐L1, HLA E, and/or HLA‐G.

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