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- Wanders, A., et al.
(författare)
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Effect of LS-2616 on the graft protection achieved by cyclosporin A, prednisolone, and 15-deoxyspergualin in heart-transplanted rats
- 1992
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Ingår i: Transpl Int. ; 5 Suppl 1, s. S462-3
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Tidskriftsartikel (refereegranskat)abstract
- The immunostimulator LS-2616 abolishes the effect of cyclosporin A in a rat cardiac transplantation model. The present paper compares the characteristics of rejection obtained under different immunosuppressive regimens with and without additional LS-2616 application in the same model. Cyclosporin A (CyA, 10 mg/kg daily), prednisolone (15 mg/kg daily), or 15-deoxyspergualin (2, 5, or 10 mg/kg daily), all given from the day of transplantation until day 9, protected the grafts during the treatment period. The addition of LS-2616 (160 mg/kg, day -1 until stop) resulted in a total abrogation of the immunosuppressive effect of CyA and prednisolone. However, LS-2616 could only partially or not at all reverse the effect of 15-deoxyspergualine. These results show a certain drug selectivity of LS-2616 in promoting rejection of immunosuppressed allografts. Further studies with LS-2616 may be of benefit in evaluating the mode of action of different immunosuppressive compounds and, thus, contribute to finding more effective antirejection therapies.
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- Wanders, A., et al.
(författare)
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Effects of prostaglandin E2 (PGE2) and drugs affecting PGE2 degradation on acute rejection of rat cardiac allografts
- 1992
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Ingår i: Scand J Thorac Cardiovasc Surg. ; 26:1, s. 33-7
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Tidskriftsartikel (refereegranskat)abstract
- Systemic administration of prostaglandin E2 (PgE2) has been reported to prolong graft survival of heart transplants. We investigated the influence of systemic injection of two compounds which inhibit the endogenous degradation of PgE2 (CL42A and CL68A) and of local infusion of PgE2 into the transplant on the survival time of rat cardiac allografts. Both CL42A and CL68A gave increased graft survival time in two rat strain combinations, though this was not predictable in individual rats. Locally infused PgE2 gave slight, but not significant prolongation of graft survival in some recipients. Combined PgE2 and cyclosporin A, however, gave significant prolongation of graft survival time compared with cyclosporin A treatment alone. When local PgE2 treatment was begun 5 days after transplantation, graft survival time was prolonged in almost all the rats. Manipulation of the local PgE2 concentration thus seemed to have a positive effect on graft survival, possibly due to down-regulation of certain cells of the immune system by PgE2.
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- Wanders, A., et al.
(författare)
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Enhancement of the effect of low-dose cyclosporin A by sulphasalazine in prevention of cardiac allograft rejection in the rat
- 1992
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Ingår i: Transpl Int. ; 5:3, s. 155-8
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Tidskriftsartikel (refereegranskat)abstract
- Sulphasalazine (SASP) is an immunomodulatory compound with disease-modifying activity in ulcerative colitis and in other autoimmune disorders. SASP was previously shown to prolong the survival of heart allografts in rats treated with cyclosporin A (CyA) for 9 days after transplantation. We have now evaluated whether SASP also exerts a beneficial effect under continuous treatment with CyA, when CyA is discontinued after 14 days, or alone if given 10 days prior to transplantation. Cardiac grafts were transplanted from PVG donors to Wistar/Kyoto recipients using an accessory cervical heart transplantation technique. Rejection was defined as the absence of palpable contractions and occurred in the control group in a very reproducible manner on day 8 or 9. SASP alone was given orally (100 mg/kg body weight) starting 10 days before transplantation and resulted in a minor prolongation of graft survival. When SASP was given in addition to oral CyA (1 mg/kg or 2 mg/kg from day 0 to rejection) there was a significant prolongation in graft survival [from medians of 8 (range 6-11) and 9 (range 8-11) days, respectively, to medians of 10 (range 8-15) and 12 (range 11-15) days, respectively]. When SASP was given from day 0 to rejection, in addition to a schedule of oral CyA (10 mg/kg) for 15 days, there was no prolongation of graft survival [median of 30 (range 26-42) days vs median of 32 (26-38) days]. The data show that SASP acts as a weak immunosuppressive agent which enhances the effect of CyA given at a low dose.(ABSTRACT TRUNCATED AT 250 WORDS)
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- Wanders, A., et al.
(författare)
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Evidence that LS-2616 (linomide) causes acute rejection of rat allografts protected by cyclosporine but not of long-term surviving allografts
- 1991
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Ingår i: Transplantation. - 0041-1337 .- 1534-6080. ; 52:2, s. 234-8
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Tidskriftsartikel (refereegranskat)abstract
- The immunomodulator LS-2616 (Linomide) induces rejection of cyclosporine-protected rat cardiac allografts. The aim of this study was to characterize this rejection in the presence of CsA and to test LS-2616 in other models of permanent graft acceptance in the rat. PVG rat hearts were transplanted heterotopically to Wistar/Kyoto (Wi/Ky) rat recipients on day 0. The recipients were treated orally on days 0-9 with CsA (10-40 mg/kg) and/or with LS-2616 (2.5-160 mg/kg) starting at different times (day -7 -+5) until the day of complete rejection. The addition of LS-2616 (day -1--stop) to CsA (10 mg/kg) resulted in a dose-dependent antagonism of the immunosuppressive effect of CsA with daily doses of 2.5-160 mg/kg. Furthermore, the results were similar, irrespective of whether LS-2616 treatment (160 mg/kg) was started on day -7, -1, +1, +3, or +5. LS-2616 (160 mg/kg) pretreatment of the recipient for 7 days before transplantation was considerably less effective. CsA (20 mg/kg) for 14 days after a PVG to DA transplantation resulted in permanent graft survival. This was not abrogated by LS-2616. Neither was rejection induced in long-term surviving grafts of RT1.C incompatible Lewis recipients. Our data suggest that LS-2616 activates already stimulated and sensitized T cells that are otherwise controlled by CsA.
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- Wanders, A., et al.
(författare)
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Expression of an interferon-gamma-like substance in normal and transplanted rat heart tissue
- 1992
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Ingår i: J Heart Lung Transplant. ; 11:1 Pt 1, s. 142-6
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Tidskriftsartikel (refereegranskat)abstract
- The presence of interferon-gamma-like molecules has been reported not only in lymphocytes, but also in certain nerve cells and in normal skeletal muscle. We have studied the reactivity of the anti-interferon-gamma monoclonal antibody DB1 with frozen sections of normal and transplanted rat hearts. Cardiac grafts from PVG donor rats were transplanted to syngeneic PVG recipients or allogeneic Wistar/Kyoto recipient rats with the use of an accessory cervical heart transplantation technique. The allogeneic heart transplants were harvested 4 days and the syngeneic grafts 4 weeks after transplantation. In normal hearts there was a weak but distinct reactivity with the anti-interferon-gamma antibody in most muscle cells. In addition, some lymphocytes and the Purkinje fibers were positive. Hearts transplanted over an allogeneic barrier revealed that staining for interferon-gamma on muscle cells was substantially increased whereas no or only a moderate increase in the anti-interferon-gamma staining was seen in hearts transplanted to syngeneic recipients. These data indicate that interferon-gamma present in rat myocyte may be involved in the pathophysiology of graft rejection and also suggest that interferon-gamma may be of importance for the function of normal rat heart muscle cells.
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