Michel Vandeputte

Prevention of murine experimental allergic encephalomyelitis: cooperative effects of cyclosporine and 1 α, 25-(OH)2D3

The hormone 1 alpha, 25-dihydroxyvitamin D3 (1,25(OH)2D3) has immune modulatory activities in vitro and in vivo, and can prevent or delay the onset of experimental or spontaneous autoimmune diseases. At therapeutical doses, however, hypercalcemic side effects are found. The present experiments examined the effects of combined treatment with subtherapeutic doses of cyclosporine A (CsA) and 1,25(OH)2D3 on the evolution of experimental autoimmune encephalomyelitis (EAE) in SJL mice. 1,25(OH)2D3 at 5 micrograms/kg body weight (given by i.p. injection every 2 days) prevented the appearance of paralysis in 70% of the treated mice. The treatment with 1,25(OH)2D3 at 2 micrograms/kg/2 days alone had less substantial protective effects (22% disease-free animals versus 5% in the control group). However, when this subtherapeutic dose was associated to treatment with a daily dose of CsA (2 or 5 mg/kg/day), which by itself was subtherapeutic (24 and 50% disease-free animals, respectively), the association of both drugs led to near-total protection (86% disease-free animals when combined with the highest dose of CsA). When an alternate day administration schedule (CsA at 10 mg/kg and 1,25(OH)2D3 at 2 micrograms/kg, each given on alternate days from day -3 to +19 after disease induction) was used, all treated mice were completely protected clinically and histologically. The two drugs also showed additive effects on serum osteocalcin and urinary calcium and desoxypyridinoline excretion, but not on serum calcium concentration. Our experiments demonstrate that 1,25(OH)2D3 might be a potential dose-reducing agent for CsA in immunosuppressive therapy.

Prolongation of allogeneic heart graft survival in the rat after implantation on portal vein.

In rats, heart allografts with venous drainage via the portal vein were performed and compared with similar grafts draining into the inferior vena cava. A new technique was developed using the complete thoracic descending aorta and ligation of all its branches. The descending thoracic aorta was anastomosed to the recipients abdominal aorta below the left renal vein. The pulmonary artery was implanted on the portal vein in an end to side fashion. In two rat strain combinations the allograft survival time was significantly prolonged when compared to that of the control grafts with pulmonary-caval anastomosis. The presumed mechanism for this prolonged graft survival might be the sequestration or degradation of transplantation antigens in the liver during their first passage through this organ. In this way only a small amount of antigen reaches the systemic circulation.

Transplantation Tolerance and Autoimmunity After Xenogeneic Thymus Transplantation

Successful grafting of vascularized xenografts (Xgs) depends on the ability to reliably induce both T cell-independent and -dependent immune tolerance. After temporary NK cell depletion, B cell suppression, and pretransplant infusion of donor Ags, athymic rats simultaneously transplanted with hamster heart and thymus Xgs developed immunocompetent rat-derived T cells that tolerated the hamster Xgs but provoked multiple-organ autoimmunity. The autoimmune syndrome was probably due to an insufficient development of tolerance for some rat organs; for example, it led to thyroiditis in the recipient rat thyroid, but not in simultaneously transplanted donor hamster thyroid. Moreover, grafting a mixed hamster/rat thymic epithelial cell graft could prevent the autoimmune syndrome. These experiments indicate that host-type thymic epithelial cells may be essential for the establishment of complete self-tolerance and that mixed host/donor thymus grafts may induce T cell xenotolerance while maintaining self-tolerance in the recipient.

The effect of heterologous antilymphocytic serum on the oncogenic activity of polyoma virus.

Abstract The action of ALS on the induction of primary polyoma tumors was investigated. ALS treatment proved to have a more efficient immuno-suppressant effect than surgical thymectomy and markedly increased the sensitivity of rats for the oncogenic activity of polyoma virus. ALS given as late as a week after the virus inoculation had still a very pronounced effect on the tumor induction.

Yolk sac derived teratomas and carcinomas in hamsters

Abstract The induction as well as the histology of visceral yolk sac derived benign teratomas in hamsters is described. The teratomas are characterized by the presence of adult well-differentiated tissues derived from all three germ layers. In these teratomas malignant transformation to yolk sac carcinoma was occasionally observed. The histogenesis of this malignant tumor is described and its origin discussed in relation to viral induced yolk sac carcinoma.

Pathogenesis of Autoimmunity After Xenogeneic Thymus Transplantation

Thymus transplantation is a promising strategy to induce xenotolerance, but may also induce an autoimmune syndrome (AIS). The pathogenesis of this AIS was explored using nude rats as recipients. Thymus grafts consisted of fetal hamster thymic tissue with or without mixing with fetal rat tissue such as thymus, thyroid, salivary gland, and heart. All hamster thymus recipients died of AIS within 2–3 mo. In most recipients of xenothymus mixed with rat tissues such as thymus, thyroid, and salivary gland, but not heart, AIS was prevented, indicating an insufficient presence of rat epithelial cell Ags within the xenothymus. AIS could be transferred to control nude rats by whole splenocytes or by splenocyte subpopulations such as CD3+, CD3−, and B lymphocytes, but not by non-T, non-B cells from AIS animals. This transfer could be suppressed by cotransferring either CD4+ or CD8+ lymphocytes from euthymic rats, but not by splenocytes from recipients of syngeneic or xenogeneic thymus mixed with rat tissue, indicating a defective generation of regulatory lymphocytes. As for CD4+ regulatory cells this defect was probably qualitative, because the percentages of CD4+CD25+ or CD4+CD45RClow populations were normal after xenothymus transplantation. As for the CD8+ regulatory cells, the defect was quantitative, as CD8+ cell levels always remained low. The latter was related to the nonvascularized nature of thymus grafts. In conclusion, AIS after xenothymus transplantation in nude rats is due to a combination of insufficient intrathymic presence of host-type epithelial cell Ags and a defective generation of regulatory T lymphocytes.

Immunological and clinical observations in diabetic kidney graft recipients pretreated with total-lymphoid irradiation

In a feasibility study, twenty patients with end-stage diabetic nephropathy were treated with fractionated total-lymphoid irradiation (TLI, mean dose 25 Gy), before transplantation of a first cadaveric kidney. During radiotherapy, only one patient had a serious side effect (bone marrow depression). After transplantation four patients died (one of a myocardial infarction, one of ketoacidosis, and two of infections occurring during treatment of rejection crises). One graft was lost because of chronic rejection. The other 15 patients have a functioning graft (mean follow-up 24 months) and receive low-dose prednisone alone (<10 mg/day, n=ll) or in conjunction with cyclosporine (n=4) as maintenance immunosuppressive therapy. A favorable clinical outcome after TLI (no, or only one, steroid-sensitive rejection crisis) was significantly correlated with (1) a high pre-TLI helper/suppressor lymphocyte ratio, (2) a short interval between TLI and the time of transplantation, and (3) the occurrence of functional suppressor cells early after TLI. The most striking immunological changes provoked by TLI consisted of a long-term depression of the mixed lymphocyte reaction and of the phytohemagglutinin, and Concanavalin A or pokeweed-mitogen-induced blastogenesis. A rapid and complete recovery of the natural killer cell activity was observed after TLI. A permanent inversion of the OKT4+ (T helper/inducer) over OKT8+ (T suppressor/cytotoxic) lymphocyte ratio was provoked by a decrease of the OTK4+ subpopulation, together with a supranormal recovery of the OKT8+ lymphocytes. A majority of the latter lymphocytes did also express the Leu 7 and the Leu 15 phenotype.

Inhibition of polyoma-virus oncogenesis in rats by polyriboinosinic-ribocytidylic acid☆

Abstract Polyriboinosinic-ribocytidylic acid (In.Cn) markedly reduced the incidence of tumors in rats injected with polyoma virus. This protective effect was observed not only when In.Cn was given before and immediately after the virus inoculation but was also recorded when In.Cn treatment was started 7–21 days afterwards. This finding strongly indicates that other mechanisms than an interferon antiviral mechanism are responsible for the observed protective effect. As In.Cn did not seem to exert a direct antitumor effect on transplantable polyoma tumors in the rat, it is very likely that its inhibitory action on polyoma oncogenesis in rats is due to an increase of the immunologic response in the host.

Effect of staphylococcal enterotoxin B injection on the development of experimental autoimmune encephalomyelitis: influence of cytokine and inducible nitric oxide synthase production

Possible mechanisms involved in the protective effect of staphylococcal enterotoxin B (SEB) injection on the subsequent development of experimental autoimmune encephalomyelitis (EAE) were investigated. Only partial clonal deletion and anergy of Vbeta8 + T-lymphocytes were documented after myelin basic protein immunization in SEB injected mice. Brain permeability was not influenced. Within the brain or during in vitro rechallenge assays SEB protected mice produced significantly more IL-10, IL-4, TNF-alpha and iNOS. It is suggested that the immune deviating effect of SEB may be involved in its EAE protective effect.

Experimental rat model for human yolk sac tumor

The morphological and biological characteristics of experimentally induced rat yolk sac carcinomas (ysca) are compared to those of human yolk sac tumors. It is shown that the rat ysca shares many morphological and biological properties with its human counterpart although the cellular origin is probably different. Whereas the human yolk sac tumors are believed to be of germ cell origin, the rat visceral yolk sac-derived tumors are not. The hypothesis is formulated that the rat ysca are derived from multipotential cells different from germ cells, and which originate in the extra-embryonic membrane after displacement.