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M Vandeputte

Publications and source records attributed to M Vandeputte.

At least 37 records · Page 2Linked to original sources
PubMed1997

Natural killer cell- and macrophage-mediated rejection of concordant xenografts in the absence of T and B cell responses.

Hyperacute, complement-mediated xenograft (Xg) rejection is a first major hurdle for xenotransplantation. Thereafter, cellular immunity, including T and B lymphocytes, NK cells, and macrophages may become involved as well. In the present study, hamster heart Xgs were performed in Leflunomide (LF)-treated nude rats. These animals, which are genetically T cell deficient, are known to have a strong NK activity. Moreover, xenoantibody (XAb) formation by B lymphocytes was previously shown to be blocked in nude rats by LF. Hence, this model was well suited to study the role of NK cells and macrophages in Xg rejection. Despite a total suppression of XAb formation, LF-treated nude rats rejected hamster heart Xgs at a same speed (3 days) as untreated nude rats. NK cells played a major role in this rejection process. Indeed, an NK cell-dominated cellular infiltration was noticed in the rejected Xgs and the addition of an anti-NK cell serum, anti-Asialo GM-1 (ASGM-1), to the LF treatment resulted in a significant delay of Xg rejection (from 3 days to 6 days; p < 0.0001) that seemed to be mediated by activated macrophages because 1) spleens from rejecting animals showed an increased percentage of macrophages (ED1+ or ED2+) and 2) rejected Xgs were infiltrated predominantly by macrophages. Moreover, splenocytes taken from rats that rejected Xgs despite a treatment with LF + ASGM-1 provoked an acceleration of Xg rejection when transferred to newly transplanted LF + ASGM-1-treated nude rats, and finally, the latter accelerating effect disappeared when macrophages were first depleted from the adoptively transferred splenocytes. This study thus shows that NK cells and macrophages can be activated in the absence of T cells or XAbs to directly reject Xgs.

Adoptive Transfer↗
PubMed1997

Accelerated collagen-induced arthritis in IFN-gamma receptor-deficient mice.

Collagen-induced arthritis (CIA) is a model for rheumatoid arthritis. Here, we describe experiments showing that IFN-gamma receptor knockout (IFN-gammaR alpha KO) mice of the DBA/1 strain develop CIA more readily than their wild-type counterparts. Symptoms of disease started 10 days earlier and the cumulative incidence of arthritis was significantly higher in the mutant mice than in wild-type mice. Similarly, accelerated onset of the disease was also found in wild-type DBA/1 mice treated with neutralizing mAbs against IFN-gamma. Histologic examination of the joints revealed a massive infiltration of the synovium with mononuclear cells and neutrophils, hyperplasia, and severe pannus formation in IFN-gammaR alpha KO mice when such inflammatory lesions were not yet detectable in wild-type mice. Serum levels of anti-collagen type II Abs, including total IgG and IgM, as well as IgG1, IgG2a, and IgG2b isotypes were found to be lower in the mutant mice. IL-2 and IL-4 remained undetectable in sera of both groups of mice, but did appear in the circulation after anti-CD3 Ab challenge. Significantly higher IL-2 and lower IL-4 serum levels were found in anti-CD3-challenged IFN-gammaR alpha KO mice than in wild-type counterparts, both at an early and at a later stage of the disease. These observations indicate that endogenous IFN-gamma counteracts development of collagen-induced arthritis and suggest that IFN-gamma does so by up-regulating IL-4 production and/or down-regulating IL-2 production. The data are in line with the concept of a pathogenic role of Th1-type cellular immunity in CIA in spite of a decreased Ab response to collagen type II.

Animals↗
PubMed1997

Activities of various compounds against murine and primate polyomaviruses.

Polyomavirus infections in humans are due to BK virus (BKV) and JC virus (JCV). Diseases associated with human polyomaviruses occur mostly in immunocompromised adults, e.g., progressive multifocal leukoencephalopathy (PML), caused by JCV, in AIDS patients and hemorrhagic cystitis and uretral stenosis, caused by BKV, in transplant recipients. No therapy is available for these diseases, which necessitates the development of chemical entities that are active against polyomaviruses. Several antiviral compounds were evaluated to determine their effects on the in vitro replication of mouse polyomavirus and the primate viruses simian virus 40 (SV40), SV40 PML-1, and SV40 PML-2. The activity of the different compounds was assessed by a cytopathic effect reduction assay and confirmed in a virus yield assay. Cidofovir [HPMPC; (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine] and its cyclic counterpart emerged as the most selective antipolyomavirus agents. The 50% inhibitory concentrations for HPMPC were in the range of 4 to 7 micrograms/ml, and its selectivity index varied from 11 to 20 for mouse polyomavirus and from 23 to 33 for SV40 strains in confluent cell monolayers. Cell cytotoxicity was up to 15-fold greater in growing cells. Other acyclic nucleoside phosphonates (i.e., HPMPA; [(S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine] and PMEG [9-(2-phosphonylmethoxyethyl)-guanine]) also showed some activity but had low selectivity. None of the other drugs tested against these animal viruses (i.e., acyclovir, ganciclovir, brivudine, ribavirin, foscarnet, and cytarabine) showed significant activity. Thus, HPMPC deserves further evaluation as a candidate drug for polyomavirus infections in the immunocompromised host.

Animals↗
PubMed1996

A short-term combination therapy with cyclosporine and rapamycin or leflunomide induces long-term heart allograft survival in a strongly immunogenic strain combination in rats.

Synergism between cyclosporine (CsA) and rapamycin (RAPA) or leflunomide (LF) was studied in a strongly immunogenic cardiac allograft model in rats. In the absence of immunosuppression, PVG recipients rejected WKAH heart grafts after a mean survival time (MST) of 5.2 +/- 1.1 days. A dose of 7.5 mg/kg per day CsA did not prolong graft survival (MST 5.6 +/- 1.2 days). CsA given at 10 mg/kg per day for 30 days extended MST of the grafts to 48 +/- 7 days. A short course of combination therapy consisting of adding a non-therapeutic dose of RAPA or a subtherapeutic dose of LF to a 1-month course of CsA resulted in permanent graft survival. These data suggest that RAPA and LF synergize with CsA enabling not only the lowering of the dose of CsA, but also inducing transplantation tolerance.

Animals↗
PubMed1996

Normal and malignant trophoblasts do not recruit granulated metrial gland cells.

A possible relationship between the development of granulated metrial gland (GMG) cells and trophoblast was studied. Trophoblast implanted in ectopic sites (e.g. kidney capsule) did not induce decidua and did not recruit GMG cells. Only when injected in utero did trophoblast lead to the development of decidua and to the recruitment of GMG cells. With malignant trophoblast (choriocarcinoma cells) similar results were obtained as with normal trophoblast both after ectopic or after in utero injection. The presence of decidua, but not the development of a conceptus or the outgrowth of trophoblast, seems to be required for the differentiation of GMG cells.

Animals↗
PubMed1995

The human immunodeficiency virus(HIV) inhibitor 9-(2-phosphonylmethoxyethyl)adenine (PMEA) is a strong inducer of differentiation of several tumor cell lines.

9-(2-phosphonylmethoxyethyl)adenine (PMEA) is the prototype compound of a series of acyclic nucleoside phosphonate derivatives endowed with potent and selective anti-retroviral activity in vitro and in vivo. We have now found that PMEA is also a potent inducer of differentiation of a number of tumor cells, including human erythroleukemia K562 cells, rat choriocarcinoma RCHO cells and human acute promyelocytic leukemic HL-60 cells. At 10 microM PMEA, rat RCHO cell cultures could be almost fully differentiated, and at 50 microM PMEA, approximately 50% of the K562 cells could be triggered to produce hemoglobin. The differentiating activity of butyric acid was at least partially additive to that of PMEA when both drugs were combined in K562 cell cultures. PMEA needs to be present for at least 2 or 3 days in the K562 cell cultures to achieve optimal differentiating activity. This suggests that either a PMEA metabolite and/or its anti-metabolic effects may be responsible for differentiation of the tumor cells.

Adenine↗
PubMed1995

Prevention of murine experimental allergic encephalomyelitis: cooperative effects of cyclosporine and 1 alpha, 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.

Amino Acids↗
PubMed1995

Effect of leflunomide and cyclosporine on the occurrence of chronic xenograft lesions.

Recently we and others have shown that a combination therapy of cyclosporine (CsA) together with anti-B lymphocyte immunosuppressants such as cyclophosphamide (CY) or leflunomide (LF) resulted in a complete suppression of xenoantibody formation and long-term heart graft survival in a hamster to rat xenograft model. Here we show that three months after transplantation, functioning xenografts may develop signs of chronic vascular and/or interstitial lesions depending on the immunosuppressants used. A combination maintenance therapy of CsA (10 mg/kg/day) together with LF (10 mg/kg/day, continuously) resulted in a healthy interstitium and normal blood vessels without signs of chronic rejection. When LF was stopped after one month of therapy but CsA continued for the whole observation period, only some local interstitial fibrosis was noticed. In contrast, when CsA was stopped after one month but LF continued, a pronounced infiltration with mononuclear cells was found, together with clear intima proliferation and severe fibrosis. In conclusion, long-term surviving xenografts may offer a new model to study the pathogenesis and therapeutic approach of chronic transplant lesions. In this model, a maintenance therapy of CsA and LF was able to prevent all signs of chronic rejection.

Animals↗
PubMed1994

Clonal deletion and clonal anergy in allogeneic bone marrow chimeras prepared with TBI or TLI.

The evolution of Vbeta6-expressing C3H (H2k, Thy 1.2, Mls a-) lymphocytes was investigated in C3H recipients mice pretreated with total body irradiation (TBI) or total lymphoid irradiation (TLI) and infusion of AKR (H2k, Thy 1.1, Mls a+) cells. After TBI (9.5 Gy) all Vbeta6+ Thy 1.2 (C3H) cells, which are capable of reacting against the Mls a antigen that like expressed by AKR mice, were deleted in the thymus and the periphery in stable bone marrow (BM) chimeras obtained by infusion of 5 x 10(6) T-cell-depleted (TCD) AKR BM cells. When, in the opposite combination, 30 x 10(6) C3H spleen cells were infused into TBI-treated AKR cells, all animals developed graft-versus-host disease (GVHD) with no clonal deletion and in contrast, showed an increase in Vbeta6+ C3H cells. After injection of 30 x 10(6) AKR BM cells into TLI-treated C3H mice no C3H cells were detected in the thymus and only a small percentage in the periphery. Within these C3H cells Vbeta6+ cells were only partially deleted and anergized as they did not respond in vitro after stimulation with Mls a+ AKR cells or anti-Vbeta6 mAb. Cells suppressing anti-Mls a-reacting C3H cells were not found. After injection of 15 x 10(6) AKR cells more C3H cells were found in the thymus, but only a minority of Vbeta6+ cells persisted in the periphery of these animals. In conclusion in TBI-prepared chimeras only clonal deletion occurred, whereas in TLI-prepared chimeras both clonal deletion and anergy occurred in maintaining tolerance.

Animals↗