15-Deoxyspergualin treatment of graft rejection in man: effect on mononuclear cells

Borg, Anette Johansson; Ohlman, S.

doi:10.1007/bf00336074

Cited by 2 publications

(2 citation statements)

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“…Screening the in vivo effect of DSG on other immunocompetent cells using immunofluorocytometry, we found no changes of biological significance in the distribution of T cell subpopulations (Table I). This is in agreement with others [40,46], but contrasts with observations published by Nicoletti et al [9]. Focusing on the density of cell surface antigens during DSG treatment, we did not notice down-regulation of any cell surface antigen, particularly not of MHC molecules, while rats that had reeeived long-term treatment with DSG exhibited already signs of the cumulative toxicity of the drug [9,36], Also, the number of cells positively stained with anti-MHC antibodies was unchanged, or indeed slightly increased in rats treated with DSG.…”

Section: Discussionsupporting

confidence: 94%

“…Our transfer experiments reveal an effect of DSG on T helper cells not detectable by measurement of proliferation [14,25] during activation, analysis of \L-2 receptor expression [15,40] or IL-2 production [14][15][16]19,23,36]. They provide for the first time a conclusive explanation for the therapeutic efficiency of DSG in experimental autoimmune disease and transplantation models, DSG might affect production of other inflammatory cytokines such as tumour necrosis factor-alpha (TNF-ti) or lymphotoxin.…”

Section: Discussionmentioning

confidence: 93%

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Impact of 15-deoxyspergualin on effector cells in experimental autoimmune diseases of the nervous system in the Lewis rat

Jung

Toyka

Hartung

1994

Clinical and Experimental Immunology

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SUMMARYThe influence of the immunosuppressivc antibiotic agent 15-deoxyspergualin (DSG) on macrophages and autoreactive T helper lymphocytes from Lewis rats was analysed in vitro and in vivo. DSG did not inhibit antigen-or mitogen-induced proliferation of encephalitogenic or neuritogenic T helper cell lines in vitro. However, the presence of DSG during in vitro activation of the T cells strongly suppressed or completely abrogated their capacity to induce encephalitis (EAE) or neuritis (EAN) after adoptive transfer to naive rats, although expression of activation markers or adhesion molecules on the T line blasts was not down-regulated by DSG, Like activationinduced T cell proliferation, IL-2-dependent growth of CD4^ T line cells was not affected by DSG, Preincubation of CD4^ T line cells in DSG during IL-2-driven proliferation for 48 h, however, inhibited the subsequent antigen-but not mitogen-induced activation of these T cells, although neither density of T eel) receptors nor other surface molecules involved in antigen recognition were lowered on the cells exposed to DSG. Similar to its effect in vitro, in vivo administration of DSG for 10 days even at a concentration with cumulative toxicity did not suppress in vitro proliferation of spleen cells induced by mitogen or a mitogenic combination of anti-CD2 antibodies. Furthermore, spleen cell and peripheral blood lymphocyte (PBL) surface antigens, particularly MHC molecules, were not altered by long-term treatment with DSG for 30 days. While there was a slight reduction in the number of polymorphonuclear cells in both populations, the proportion of the different leucocyte subpopulations remained unchanged. In contrast to the strong functional impact of DSG on autoreactive T helper cells, the drug did not inhibit the oxidative burst of macrophages or their MHC antigen expression. This study demonstrates a clear inhibitory effect of DSG on CD4''' T lymphocytes, but not macrophages. It provides an explanation for recent observations of a strong immunosuppressive in vivo effect of DSG on transplantation rejection and experimental autoimmune diseases, despite a normal mitogen response of T cells exposed to DSG in vivo and in vitro.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionmentioning

confidence: 93%

Impact of 15-deoxyspergualin on effector cells in experimental autoimmune diseases of the nervous system in the Lewis rat

Jung

Toyka

Hartung

1994

Clinical and Experimental Immunology

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New Immunosuppressive Drugs and Their Role in the Prevention of Islet Xenograft Rejection

Wennberg

Groth

1997

BioDrugs

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Islet transplantation offers an attractive future means to treat diabetes as long as prevention of xenograft rejection can be accomplished. This review analyses the role of 5 new immunosuppressive drugs [tacrolimus, sirolimus, mycophenolate mofetil, gusperimus (15-deoxyspergualin) and leflunomide] in the context of islet xenotransplantation. Although cytotoxic T cells are the major effector cells in allogeneic islet rejection, macrophages serve as important contributing effector cells in xenogeneic islet rejection. All the drugs discussed in this review inhibit T cell activation, and several of them also inhibit B cells. In addition, gusperimus has been found to inhibit macrophages. All the drugs have, at least in some animal model, delayed islet xenograft rejection. Synergistic, or at least additive, protective effects have been observed when 2 or more of the drugs have been used in combination. Assessment of the relative efficacy of the various drugs is made difficult by the use of different models in the various studies performed. In the future, several drugs should be examined in a single model. The efficacy of the various drugs in controlling autoimmune beta cell damage after transplantation remains poorly known. One of the drugs, tacrolimus, has the disadvantage of being diabetogenic in animals and humans. The other drugs do not disturb glucose homeostasis, at least in humans. Mycophenolate mofetil and leflunomide are antiproliferative drugs, a feature that might be disadvantageous in fetal endocrine pancreas transplantation. Although several of the newly available drugs show considerable promise in the prevention of islet xenograft rejection, the search for even better immunosuppressive drugs must continue.

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15-Deoxyspergualin treatment of graft rejection in man: effect on mononuclear cells

Cited by 2 publications

References 22 publications

Impact of 15-deoxyspergualin on effector cells in experimental autoimmune diseases of the nervous system in the Lewis rat

Impact of 15-deoxyspergualin on effector cells in experimental autoimmune diseases of the nervous system in the Lewis rat

New Immunosuppressive Drugs and Their Role in the Prevention of Islet Xenograft Rejection

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