Immunosuppressive mechanism of 15-deoxyspergualin on sinusoidal lining cells in swine liver transplantation: Suppression of MHC class II antigens and interleukin-1 production

Takasu, Shinji; Sakagami, K; Morisaki, Futoshi; Kawamura, Takumi; Haisa, Minoru; Oiwa, Takashi; Inagaki, Masaru; Hasuoka, Hideaki; Kurozumi, Yoichi; Orita, Kunzo

doi:10.1016/0022-4804(91)90089-5

Cited by 13 publications

(7 citation statements)

References 14 publications

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“…In monocytes, it has been reported that DSG inhibits IL1 production, class I (48) and class II (49) induction, antigen processing (12), and NO synthase induction (13). Macrophage activation is also inhibited by DSG.…”

Section: Discussionmentioning

confidence: 99%

Induction of Donor‐Specific Allograft Tolerance by Short‐Term Treatment with LF15‐0195 After Transplantation. Evidence for a Direct Effect on T‐Cell Differentiation

Chiffoleau

Bériou

Dutartre

et al. 2002

American Journal of Transplantation

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A 20-day treatment with LF15-0195, a deoxyspergualine analog, induced long-term heart allograft survival in the rat without signs of chronic rejection. LF15-0195-treated recipients did not develop an anti-donor alloantibody response. Analysis of graft-infiltrating cells, IL10, TNFa, IFNg mRNA and iNOS protein expression in allografts, 5 days after transplantation, showed that they were markedly decreased in allografts from LF15-0195-treated recipients compared with allografts from untreated recipients. Surprisingly, spleen T cells from LF15-0195 recipients, 5 days after grafting, were able to proliferate strongly in vitro, when stimulated with donor cells, but had reduced mRNA expression for IFNg compared with spleen T cells from untreated graft recipients. Furthermore, when T cells from naive animals were stimulated in vitro, using anti-CD3 and anti-CD28, LF15-0195 also increased T-cell proliferation in a dose-dependent fashion; however, these cells expressed less of the Th1-related cytokines, IFNg and IL2, compared with untreated cells, suggesting that LF15-0195 could act on T-cell differentiation. In conclusion, we show here that a short-term treatment with LF15-0195 induced long-term allograft tolerance, decreasing the in situ anti-donor response, and we illustrate evidence for the development of regulatory mechanisms.

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Section: Discussionmentioning

confidence: 99%

Induction of Donor‐Specific Allograft Tolerance by Short‐Term Treatment with LF15‐0195 After Transplantation. Evidence for a Direct Effect on T‐Cell Differentiation

Chiffoleau

Bériou

Dutartre

et al. 2002

American Journal of Transplantation

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“…Here, anti-C5 Ab treatment was combined with LF and CsA. LF and its analogue 15-deoxyspergualin (DSG) have documented protective effects in kidney damage and primate kidney allograft models (27)(28)(29)(30)(31), which occur through inhibition of antigen-presenting cell maturation, activation and local recruitment (29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41), and in particular, attenuation of B-cell differentiation and antibody production (32)(33)(34)(35)(36). Additionally, to attenuate T-cell alloreactivity directly, we also included CsA in the treatment regimen with LF and anti-C5 monoclonal antibody.…”

Section: Introductionmentioning

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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“…In rat Goodpas ture's syndrome, deoxyspergualin treatment suppressed TNF-a production by isolated pulmonary mononuclear cells -although the TNF-a production in response to lipo polysaccharide stimulation was not affected [29]. Similar ly, IL-1 production by isolated Kupfier cells and sinusoi dal endothelial cells in liver transplantation was sup pressed by deoxyspergualin [58]. However, the mecha nism of this cytokine inhibition is unclear, since 3-day culture of human monocytes or inyelomonocytic cell lines with deoxyspergualin does not affect constitutive trans forming growth factor beta-1 mRNA expression or lipopolysaccharide-induced secretion of IL-1 (3, IL-6, or TNFa [59], Similarly, we have found no effect of deoxysper gualin upon constitutive or inducible cytokine gene ex pression by rat mesangial cells.…”

Section: Cytokine Productionmentioning

confidence: 48%

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

Kerr

Lan

Tesch

et al. 1995

Nephron

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Immunosuppressive mechanism of 15-deoxyspergualin on sinusoidal lining cells in swine liver transplantation: Suppression of MHC class II antigens and interleukin-1 production

Cited by 13 publications

References 14 publications

Induction of Donor‐Specific Allograft Tolerance by Short‐Term Treatment with LF15‐0195 After Transplantation. Evidence for a Direct Effect on T‐Cell Differentiation

Induction of Donor‐Specific Allograft Tolerance by Short‐Term Treatment with LF15‐0195 After Transplantation. Evidence for a Direct Effect on T‐Cell Differentiation

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

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

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