Pathogenesis and mechanisms of graft rejection in concordant xenotransplantation with special reference to hamster‐to‐rat cardiac transplantation

STEINBRÜCHEL, DANIEL A.

doi:10.1111/j.1600-0463.1996.tb05559.x

Cited by 8 publications

(2 citation statements)

References 151 publications

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“…If HAR is blocked or attenuated, xenogeneic organs will undergo AVR, also known as DXR within days following transplantation [3,4,31]. AVR is not limited to discordant xenografting, as most concordant xenografts also develop AVR [32]. AVR now represents the major obstacle to successful xenotransplantation [4,10,33].…”

Section: Discussionmentioning

confidence: 99%

Treatment with a short course of LF 15‐0195 and continuous cyclosporin A attenuates acute xenograft rejection in a rat‐to‐mouse cardiac transplantation model

Wang

Hosiawa

García

et al. 2003

Xenotransplantation

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Searching for a novel immunosuppressive agent to effectively prevent acute vascular rejection (AVR) is essential for success in clinical xenotransplantation. We previously reported that Lewis rat hearts transplanted into BALB/c mice developed typical AVR in 6 days. The present study was undertaken to determine the efficacy of LF 15-0195, a new immunosuppressive analog of 15-deoxyspergualin in the prevention of AVR in a rat-to-mouse cardiac xenograft model. We transplanted 2-week old Lewis rat hearts into BALB/c mice. Four groups were included in this study: untreated recipients and cyclosporin A (CsA) treated recipients were controls; LF 15-0195 treated recipients or LF 15-0195 combined with CsA treated recipients were experimental groups. Mouse recipients received either LF 15-0195 2 mg/kg subcutaneously from day-1 to post-operative day 14, or CsA 15 mg/kg subcutaneously daily, from day 0 to endpoint rejection, or the two drugs in combination. We observed that high dose CsA did not inhibit AVR and the graft was rejected in 11.3 +/- 1.9 days. Graft histology and immunohistology showed typical AVR, characterized by interstitial hemorrhage, intravascular fibrin deposition, thrombosis, and massive deposition of anti-rat immunoglobulin G (IgG) and immunoglobulin M (IgM). Serum xenoreactive antibodies (xAbs) were markedly elevated in these animals as well. In contrast, we observed that treatment with LF 15-0195 alone significantly prolonged graft survival to 19.3 +/- 0.7 days. Notably, xAbs were significantly decreased and the rejection pattern of these grafts was cell-mediated rejection (CMR), instead of AVR. When CsA was combined with LF 15-0195, the graft mean survival time was further increased to 58.5 +/- 17.3 days. Antibody production and T-cell infiltration were significantly inhibited at the terminal stages of graft survival and pathology showed striking attenuation of both AVR and CMR. Sequential studies on days 6 and 14 demonstrated that LF 15-0195 either alone or combined with CsA completely inhibited antibody production. However, intragraft infiltration by Mac-1 positive cells including natural killer cells, macrophages and granulocytes in LF 15-0195 treated recipients was similar to that of untreated recipients. We conclude that LF 15-0195 effectively prevented AVR by markedly inhibiting the production of anti-donor IgG xAbs. Also, treatment with short course LF 15-0195 and continuous CsA significantly reduced T-cell infiltration. Studies to test this therapy in inhibiting AVR in a pig-to-non-human primate xenotransplantation model are underway.

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Section: Discussionmentioning

confidence: 99%

Treatment with a short course of LF 15‐0195 and continuous cyclosporin A attenuates acute xenograft rejection in a rat‐to‐mouse cardiac transplantation model

Wang

Hosiawa

García

et al. 2003

Xenotransplantation

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“…The function of the transplant was followed daily by abdominal palpation. The experiment finished when the heartbeat stopped as described by Steinbrüchel (1996).…”

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confidence: 99%