Use of Intravenous Immunoglobulin to Delay Xenogeneic Hyperacute Rejection an in Vivo and in Vitro Evaluation

Gautreau, C.; Kojima, Taiki; Woimant, G.; Cardoso, Jorge; Devillier, Philippe; Houssin, D

doi:10.1097/00007890-199511000-00004

Cited by 25 publications

(17 citation statements)

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“…In allotransplantation, there is some evidence of the efficacy of IVIg as an immunomodulatory agent in highly HLA-sensitized patients [43][44][45] and in the treatment of antibody-mediated rejection 46 . The effect of IVIg in xenotransplantation remains controversial, with some groups reporting a benefit 16,31,39,40 , but others reporting no benefit 18 or even harm 5 . Here, we report for the first time that most preparations of IVIg do not contain anti-TKO pig IgG/IgM, and are not cytotoxic to TKO pig cells.…”

Section: A B Discussionmentioning

confidence: 99%

“…In order to evaluate both the effect of suppressing antibody binding (i.e., idiotype) and anti-complement effect in IVIg, of titrated non-heat-inactivated human or baboon serum (i.e. complement activity + ; 450 µl) with PBS and/or titrated IVIg (0-360 µl) (FLEBOGAMMA) and 5% sorbitol (15-375 µl) was added to each tube (total 900 µl) and incubated at 37 °C for 150min 31 . When serum and IVIg were co-cultured titrated, IVIg was added instead of 5% sorbitol, which is a constituent solution of FLEBOGAMMA.…”

Section: Competitive Binding To Prbcs or Paecs Of Ivig With Igg And Imentioning

confidence: 99%

“…Titrated non-heat-inactivated serum (i.e. with complement activity; 450 µl) with PBS and 5% sorbitol (375 µl) instead of IVIg was added to each tube (total 900 µl) and incubated at 37 °C for 150min 31 . Control samples consisted of PBS (instead of the RBC solution) + 450 µl of titrated non-heat-inactivated serum with PBS + 5% sorbitol.…”

Section: Cytotoxicity Of Pooled Human Serum and Ivig To Prbcs In Ordmentioning

confidence: 99%

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Effect of intravenous immunoglobulin (IVIg) on primate complement-dependent cytotoxicity of genetically engineered pig cells: relevance to clinical xenotransplantation

Yamamoto

Cui

Patel

et al. 2020

Sci Rep

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Triple-knockout (TKO) pigs may be ideal sources of organs for clinical xenotransplantation because many humans have no preformed antibody to TKO pig cells. Intravenous immunoglobulin (IVIg) is widely used for severe infection or the treatment/prevention of antibody-mediated rejection in allotransplantation. Anti-pig antibodies in IVIg could be harmful in clinical xenotransplantation. It is unknown whether anti-TKO pig antibodies are present in IVIg. The main aim of this study was to investigate in vitro whether IVIg contains anti-TKO pig antibodies with cytotoxic effect to pig cells. Undiluted pooled human serum (HS) and five different commercial preparations of IVIg were tested for IgM and IgG binding to red blood cells (RBCs) from wild-type (WT), α1,3-galactosyltransferase gene-knockout (GTKO), and TKO pigs by flow cytometry. Complement-dependent lysis of IVIg against these pig pRBCs was measured by hemolytic assay. Pooled HS and 4 of 5 IVIg commercial preparations contained anti-pig IgG that bound to WT and GTKO pRBCs, but not to TKO pRBCs. One preparation of IVIg contained antibodies that bound to TKO pRBCs, but there was no cytotoxicity of IVIg to TKO pRBCs. The results suggest that IVIg administration to human recipients of TKO pig grafts would be safe. However, the specific preparation of IVIg would need to be screened before its administration. Abbreviations Gal Galactose-α1,3-galactose GTKO α1,3-Galactosyltransfearse gene-knockout IVIg Intravenous immunoglobulin Neu5Gc N-Glycolylneuraminic acid NHP Nonhuman primate pAECs Pig aortic endothelial cells pRBCs Pig red blood cells TKO Triple gene-knockout WT Wild-type Genetically-modified pigs could be an alternative source of organs for clinical transplantation.

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Section: A B Discussionmentioning

confidence: 99%

Section: Competitive Binding To Prbcs or Paecs Of Ivig With Igg And Imentioning

confidence: 99%

Section: Cytotoxicity Of Pooled Human Serum and Ivig To Prbcs In Ordmentioning

confidence: 99%

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Effect of intravenous immunoglobulin (IVIg) on primate complement-dependent cytotoxicity of genetically engineered pig cells: relevance to clinical xenotransplantation

Yamamoto

Cui

Patel

et al. 2020

Sci Rep

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“…The lack of complement activation by IVIg may be the result of a treatment of the commercial IVIg preparations by the manufacturer, aimed at prevention of complement activation. IVIg dose‐dependently decreased complement deposition and CDC to pig cells when added to normal human serum [32,38], although it did not block IgM binding [32]. The complement‐inhibitory effect of IVIg is probably mainly mediated via the scavenging of C1q and activated C3 and C4, thereby preventing their binding to the complement‐activating target [39–42].…”

Section: Discussionmentioning

confidence: 99%

Both IgG and IgM anti‐pig antibodies induce complement activation and cytotoxicity

Roos

Essers

Gijlswijk-Janssen

et al. 2001

Xenotransplantation

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Hyperacute rejection of pig xenografts transplanted in humans is caused by endothelial cell binding of pre-formed xenoreactive antibodies (XAb) and activation of the classical pathway of complement. Human XAb mainly consist of anti-Galalpha1 3Gal antibodies, which occur in IgM, IgG and IgA classes. Whereas IgM anti-Galalpha1 3Gal antibodies have an established role in hyperacute rejection, the potential role of IgG XAb in this process is still controversial. The aim of the present study was to assess the specificity and functional properties of IgG and IgM XAb. Both classes were present in all human plasma samples tested, with a high inter-individual variability. Levels of IgG XAb did not correlate with levels of IgM XAb. Binding to Galalpha1 3Gal is strongly correlated with binding to the pig cell line PK15, both for IgG and for IgM, pointing to Galalpha1 3Gal as the major antigen recognized. Both purified IgM and IgG induced C3 deposition on PK15 cells and complement-dependent cytotoxicity in a dose-dependent way. The combination of IgG and IgM XAb resulted in an additive effect on cytotoxicity. Affinity-purified IgG anti-Galalpha1 3Gal antibodies were 22 times less potent than IgM in induction of cytotoxicity. These results indicate a quantitative, but not a qualitative, difference between IgM and IgG anti-pig antibodies concerning their complement-activating properties. Therefore, both classes of XAb are of importance in the pathogenesis of hyperacute rejection, and the relative importance of each class may differ considerably between individual patients, depending on the ratio of IgG and IgM XAb present in serum.

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“…However, when only short survival of tiie injected cells is required, it might be easier, as a first step, to manipulate the recipient rather than the packaging cells. Indeed, ttansientiy abolishing complement activity, which is the key element in the rapid elimination of xenogeneic cells, can be safely achieved in humans by using intravenous iinmunoglobulins (Basta and Dalakas, 1994;Basta, 1996), and was shown to significantly prolong xenograft survival in animal (Gautreau et al, 1995). We are cunentiy exploring this possibility.…”

Section: Efficacymentioning

confidence: 99%

A Phase I/II Dose-Escalation Study of Herpes Simplex Virus Type 1 Thymidine Kinase “Suicide” Gene Therapy for Metastatic Melanoma

Klatzmann

Chérìn²,

Bensimon³

et al. 1998

Human Gene Therapy

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We performed a dose-escalating phase I/II study of retrovirus-mediated herpes simplex virus type 1 thymidine kinase (HSV-1-TK) suicide gene therapy for metastatic melanoma. HSV-1 TK expression, which specifically sensitizes transduced and bystander cancer cells to ganciclovir (GCV) toxicity, was mediated by one (four patients, first dose step) to three (four patients, second dose step) injections of "M11" retrovirus vector-producing cells in melanoma cutaneous nodules. After a 7-day period allowed for cancer cell transduction, GCV was administered for 14 days. Safety was assessed by clinical and laboratory evaluations, and efficacy was assessed by tumor measurements and histology. M11 doses ranged from 76 to 1247 x 10(6) cells. Treatment-related adverse events were mild and transient, limited to inflammatory skin reactions at injection and fever on repeated injections. Plasma GCV was in the active range (>0.2 microg/ml); transgene was detected by polymerase chain reaction in three of six patients; treated tumor size was moderately affected under GCV as compared with untreated tumors, although 2 weeks after GCV administration important (>50%) treated-tumor necrosis was evidenced on histology in three of eight patients. All patients showed disease progression on long-term follow-up. Thus, M11-mediated HSV-1 TK gene therapy was well tolerated over a wide dose range. The limited tumor response is likely to be related to poor gene transfer efficiency. However, necrosis following GCV administration in transduced tumors indicates a potential for treatment efficacy.

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Use of Intravenous Immunoglobulin to Delay Xenogeneic Hyperacute Rejection an in Vivo and in Vitro Evaluation

Cited by 25 publications

References 0 publications

Effect of intravenous immunoglobulin (IVIg) on primate complement-dependent cytotoxicity of genetically engineered pig cells: relevance to clinical xenotransplantation

Effect of intravenous immunoglobulin (IVIg) on primate complement-dependent cytotoxicity of genetically engineered pig cells: relevance to clinical xenotransplantation

Both IgG and IgM anti‐pig antibodies induce complement activation and cytotoxicity

A Phase I/II Dose-Escalation Study of Herpes Simplex Virus Type 1 Thymidine Kinase “Suicide” Gene Therapy for Metastatic Melanoma

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