Immunoglobulin prevents complement-mediated hyperacute rejection in swine-to-primate xenotransplantation.

Magee, John C.; Collins, Bradley H.; Harland, Robert C.; Lindman, Bonnie J.; Bollinger, R. Randal; Frank, Michael M.; Platt, Jeffrey L.

doi:10.1172/jci118297

Cited by 176 publications

(125 citation statements)

References 43 publications

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“…Ab molecules with higher affinity for C1q and higher CDC activity than wildtype IgG1 have the potential to enhance the clearance of immune complexes in several disease conditions, such as systemic lupus erythematosus (22). They may be used to inhibit complement-mediated immune cytotoxicity in certain clinical situations (e.g., xenogenic hyperacute rejection) (23,24). In addition, IgGs with increased CDC activity have been implicated in the treatment of some bacterial infections (25).…”

Section: Resultsmentioning

confidence: 99%

Engineered Antibodies with Increased Activity to Recruit Complement

Idusogie¹,

Wong²,

Presta³

et al. 2001

The Journal of Immunology

258

168

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This manuscript describes two sites in a human IgG1 that, when mutated individually or in combination, result in a dramatic increase in C1q binding and complement-dependent cytotoxicity activity. These two residues, K326 and E333, are located at the extreme ends of the C1q binding epicenter in the CH2 domain of a human IgG. A mutation to tryptophan at K326 debilitates Ab-dependent cell-mediated cytotoxicity activity. In addition, substitutions of the residues E333 with serine and of K326 with tryptophan in a human IgG2 confer biological activity in the complement-dependent cytotoxicity assay in which the wild-type IgG2 is inactive. This study reveals that the residues K326 and E333 play a significant role in the control of the biological activity of an IgG molecule and can rescue the activity of an inactive IgG isotype.

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Section: Resultsmentioning

confidence: 99%

Engineered Antibodies with Increased Activity to Recruit Complement

Idusogie¹,

Wong²,

Presta³

et al. 2001

The Journal of Immunology

258

168

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“…Hyperacute rejection can now be overcome by depletion of antidonor antibodies or inhibition of complement (3)(4)(5). When hyperacute rejection is averted, especially by inhibition of the recipient's complement system, the xenograft becomes subject to acute vascular rejection that destroys the graft over a period of hours to days (6,7). This type of rejection is now viewed as a major immunologic barrier to the clinical application of xenotransplantation.…”

Section: Introductionmentioning

confidence: 99%

The role of antibodies in acute vascular rejection of pig-to-baboon cardiac transplants.

Lin

Weidner²,

Byrne³

et al. 1998

J. Clin. Invest.

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259

161

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Long-term success in xenotransplantation is currently hampered by acute vascular rejection. The inciting cause of acute vascular rejection is not yet known; however, a variety of observations suggest that the humoral immune response of the recipient against the donor may be involved in the pathogenesis of this process. Using a pig-to-baboon heterotopic cardiac transplant model, we examined the role of antibodies in the development of acute vascular rejection. After transplantation into baboons, hearts from transgenic pigs expressing human decay-accelerating factor and CD59 underwent acute vascular rejection leading to graft failure within 5 d; the histology was characterized by endothelial injury and fibrin thrombi. Hearts from the transgenic pigs transplanted into baboons whose circulating antibodies were depleted using antiimmunoglobulin columns (Therasorb, Unterschleisshein, Germany) did not undergo acute vascular rejection in five of six cases. Biopsies from the xenotransplants in Ig-depleted baboons revealed little or no IgM or IgG, and no histologic evidence of acute vascular rejection in the five cases. Complement activity in the baboons was within the normal range during the period of xenograft survival. In one case, acute vascular rejection of a xenotransplant occurred in a baboon in which the level of antidonor antibody rose after Ig depletion was discontinued. This study provides evidence that antibodies play a significant role in the pathogenesis of acute vascular rejection, and suggests that acute vascular rejection might be prevented or treated by therapies aimed at the humoral immune response to porcine antigens. (

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“…IgG has been reported to regulate the classical complement pathway, because IgG treatment prevents complement-dependent hyperacute rejection (Magee et al, 1995). However, the classical pathway can be inhibited by IgG only at high doses (2 g/kg).…”

Section: Involvement Of Dppiv IV In Complement Cascadementioning

confidence: 99%

Involvement of Dipeptidyl Peptidase IV in Immune Complex–Mediated Glomerulonephritis

Shinosaki

Kobayashi

Kimura

et al. 2002

Laboratory Investigation

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SUMMARY:Dipeptidyl peptidase IV (DPPIV) is widely expressed in many tissues; however, its precise biological function is poorly understood. One of its possible physiologic roles is an involvement in the immune system, which plays a pivotal role in the pathogenesis of glomerulonephritis. The present study focused on the involvement of DPPIV in immune complex-mediated glomerulonephritis. Experimental nephritis was induced by anti-Thy-1.1 monoclonal antibody E30 using Wistar or F344 rats. The application of a new monoclonal antibody against DPPIV, F16, completely suppressed E30-induced proteinuria and mesangial proliferation in Wistar rats, whereas these preventive effects of F16 were not observed in F344 rats, which spontaneously lack DPPIV protein. Treatment with F16 inhibited glomerular deposition of complement C3 and complement C4 after the binding of E30 to the mesangial cell surface. Because the preventive effect of F16 was attributable to suppression of the complement cascade, we examined its influences on complement-dependent mesangial cell lysis in vitro. We discovered that the complement cascade was markedly inactivated in F16-treated Wistar rat serum but not in F16-treated F344 rats. These results indicate that DPPIV may play a somewhat crucial role in regulating the complement cascade and that inhibition of DPPIV may serve as a new target for preventing complement-dependent tissue injury. (Lab Invest 2002, 82:505-513).

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Immunoglobulin prevents complement-mediated hyperacute rejection in swine-to-primate xenotransplantation.

Cited by 176 publications

References 43 publications

Engineered Antibodies with Increased Activity to Recruit Complement

Engineered Antibodies with Increased Activity to Recruit Complement

The role of antibodies in acute vascular rejection of pig-to-baboon cardiac transplants.

Involvement of Dipeptidyl Peptidase IV in Immune Complex–Mediated Glomerulonephritis

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