Prolongation of Xenograft Survival After Combination Therapy With 15-Deoxyspergualin and Total-Lymphoid Irradiation in the Hamster-to-Rat Cardiac Xenograft Model

Marchman, W.; Araneda, D; DeMasi, Richard J.; Taylor, Derek J.; Larkin, Ernest W.; Alqaisi, Munther; Thomas, Francis T.

doi:10.1097/00007890-199201000-00005

Cited by 33 publications

(12 citation statements)

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“…CsA, although acting primarily on Tcell activation and proliferation, can also reduce antibody responses through IL-4 inhibition (50). The potencies of DSG and LF were first demonstrated by their successful attenuation of acute vascular rejection in both rodent (51)(52)(53) and primate xenotransplantation models (54,55). Recently, LF was shown to significantly prolong renal allograft survival in monkeys (27,28) and to induce donor-specific cardiac allograft tolerance in mice (56,57) and rats (36,(58)(59)(60)(61)(62).…”

Section: Discussionmentioning

confidence: 99%

C5 Blockade with Conventional Immunosuppression Induces Long-Term Graft Survival in Presensitized Recipients

Rother

Arp

Jiang

et al. 2008

American Journal of Transplantation

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We explored whether a functionally blocking anti-C5 monoclonal antibody (mAb) combined with T- and B-cell immunosuppression can successfully prevent antibody-mediated (AMR) and cell-mediated rejection (CMR) in presensitized murine recipients of life-supporting kidney allografts. To mimic the urgent clinical features of AMR experienced by presensitized patients, we designed a murine model in which BALB/c recipients were presensitized with fully MHC-mismatched C3H donor skin grafts one week prior to C3H kidney transplantation. Presensitized recipients demonstrated high levels of circulating and intragraft antidonor antibodies and terminal complement activity, rejecting grafts within 8.5 +/- 1.3 days. Graft rejection was predominantly by AMR, characterized by interstitial hemorrhage, edema and glomerular/tubular necrosis, but also demonstrated moderate cellular infiltration, suggesting CMR involvement. Subtherapeutic treatment with cyclosporine (CsA) and LF15-0195 (LF) did not significantly delay rejection. Significantly, however, the addition of anti-C5 mAb to this CsA/LF regimen prevented terminal complement activity and inhibited both AMR and CMR, enabling indefinite (>100 days) kidney graft survival despite the persistence of antidonor antibodies. Long-term surviving kidney grafts expressed the protective proteins Bcl-x(S/L) and A-20 and demonstrated normal histology, suggestive of graft accommodation or tolerance. Thus, C5 blockade combined with routine immunosuppression offers a promising approach to prevent graft loss in presensitized patients.

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Section: Discussionmentioning

confidence: 99%

C5 Blockade with Conventional Immunosuppression Induces Long-Term Graft Survival in Presensitized Recipients

Rother

Arp

Jiang

et al. 2008

American Journal of Transplantation

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“…This classification is based upon the disparity between the donor and recipient species and the presence or absence of preformed antibodies aimed at donor cells in the recipient blood. In the concordant xenograft rejection, humoral immunity is thought to be the primary response and cellular immunity the secondary response [2][3][4]. Thus, in untreated animals rejection will occur after a period of a few days when sufficient levels of antibodies have been formed to cause graft failure [5,6].…”

Section: Introductionmentioning

confidence: 99%

A Morphological Sequential Study of Mouse‐to‐Rat Cardiac Xenografts

et al. 1998

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Long-term survival of a concordant xenograft can be achieved by using cyclosporine (CyA) and deoxyspergualin (DSG) for immunosuppression. We have demonstrated in a mouse-to-rat heterotopic heart transplantation model that DSG treatment can be stopped after 4 weeks with the grafts remaining beating. In this investigation we have sequentially characterized the morphological changes and infiltrating cells in the transplanted hearts. Graft recipients were killed 9 days, 28 days and 56 days after transplantation. At days 9 and 28, the grafts exhibited a well-preserved morphology, with infiltrating cells restricted only to the periphery. These cells stained positive for rat MHC class II antigens, the ED1-macrophage marker and the CD4 antigen, and were thus considered to be macrophages. In comparison, grafts harvested at day 56 had signs of interstitial fibrosis and some arteries showed pronounced intimal thickening. There was a moderate infiltrate of cells both in the peripheral and central parts of the graft, consisting mainly of MHC class II+/ CD4+/ED1+ macrophages. Very few T cells and NK cells were noticed. Termination of DSG after 28 days does not trigger a humoral rejection. However, the grafts exhibit morphological changes equivalent to those seen in chronic allograft rejection. In addition, the characteristics of the infiltrating cells conformed with cellular infiltrates associated with chronic allograft rejection. Hence, this model could in the future prove to be useful for studies of mechanisms involved in chronic xenograft rejection.

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“…In these studies, deoxyspergualin administered at 2-5 mg/kg has proven to be as efficacious or better than ciclosporin A and FK506 [9], while combinations of deoxyspergualin with ciclosporin A and/or steroids have provided addi tional benefit [10], In models of xenotransplantation, monotherapy with deoxyspergualin has produced mixed results; however, it has been shown to markedly enhance the suppressive ability of other monotherapies [11][12][13][14]. A second very important feature of the deoxyspergualin action is its ability to reverse established acute rejection [15].…”

Section: Experimental Transplantationmentioning

confidence: 99%

Deoxyspergualin: A New Immunosuppressive Drug for the Treatment of Auto-Immune Disease

Kerr

Lan

Tesch

et al. 1995

Nephron

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Prolongation of Xenograft Survival After Combination Therapy With 15-Deoxyspergualin and Total-Lymphoid Irradiation in the Hamster-to-Rat Cardiac Xenograft Model

Cited by 33 publications

References 0 publications

C5 Blockade with Conventional Immunosuppression Induces Long-Term Graft Survival in Presensitized Recipients

C5 Blockade with Conventional Immunosuppression Induces Long-Term Graft Survival in Presensitized Recipients

A Morphological Sequential Study of Mouse‐to‐Rat Cardiac Xenografts

Deoxyspergualin: A New Immunosuppressive Drug for the Treatment of Auto-Immune Disease

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