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M Waer

Publications and source records attributed to M Waer.

At least 91 records · Page 5Linked to original sources
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

Differentiation induction of human leukemia cells (HL60) by a combination of 1,25-dihydroxyvitamin D3 and retinoic acid (all trans or 9-cis).

1,25(OH)2D3 and two stereoisomers of retinoic acid, all trans and 9-cis retinoic acid, are regulators of cell proliferation and differentiation. The aim of this study was to evaluate the effects of a combination of 1,25(OH)2D3 and retinoic acid (all trans or 9-cis) on proliferation and cell differentiation of the human promyelocytic leukemia cell line HL60, and to test the reversibility of the induced differentiation. Cell proliferation was inhibited as expected by 1,25(OH)2D3 and all trans retinoic acid alone (IC50 of cell survival was 4 x 10(-7) M, 9 x 10(-6) M and 9 x 10(-7) M for 1,25(OH)2D3, all trans and 9-cis retinoic acid, respectively). Combination of 1,25(OH)2D3 and either form of retinoic acid resulted in a partially additive decrease in cell proliferation. 1,25(OH)2D3 induced a monocytic differentiation (100% CD14+ cells with 10(-7) M 1,25(OH)2D3), while retinoic acid led to a predominantly granulocytic differentiation (36 and 42% CD67+ cells with 10(-6) M all trans and 9-cis retinoic acid, respectively). Additive effects on differentiation were observed upon combination of subtherapeutical doses of the drugs, achieving a mainly monocytic population, demonstrating the dominant role of 1,25(OH)2D3 in determining the direction of differentiation. The effects on proliferation and differentiation of the solitary drugs were reversible, while the proliferation arrest and differentiation induced by the combination persisted and even progressed after withdrawal of the drugs. We conclude that 1,25(OH)2D3 and retinoic acid (all trans or 9-cis) exert additive effects on inhibition of proliferation and induction of cell differentiation of HL60 cells, leading to a persistent differentiation, even after drug withdrawal.

Antigens, CD↗
PubMed1995

Immunomodulatory effects of 1,25-dihydroxyvitamin D3.

The activated form of vitamin D, 1,25-dihydroxyvitamin D3, has not only a central role in bone and calcium metabolism, but also has important general effects on cell proliferation and differentiation. Moreover, 1,25-dihydroxyvitamin D3 behaves as a paracrine factor in the immune system as it can be produced by monocytes and has potent actions on all the cellular components of the immune defence system. In recent years, this new physiological role has been studied intensively both in terms of research and with the purpose of exploiting this action in a (pre)clinical setting. Indeed, through chemical alterations of the parent molecule, new substances have been created, called vitamin D analogues. Some of these molecules share the immunological effects of the mother compound, but have decreased effects on calcium and bone metabolism. This makes them potentially useful in clinical practice as immunomodulatory drugs. In the present review, we summarize the data on the in-vitro immune effects of 1,25-dihydroxyvitamin D3 and its analogues and demonstrate that these compounds have clear in-vivo immune modulating properties in the prevention of spontaneous and allergic autoimmune diseases and in the prevention of graft rejection.

Adjuvants, Immunologic↗
PubMed1995

Prevention of type I diabetes in NOD mice by nonhypercalcemic doses of a new structural analog of 1,25-dihydroxyvitamin D3, KH1060.

Pharmacological amounts of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] have potent immunoregulatory activity, but with marked effects on calcium and bone metabolism. In this study we demonstrate that nonhypercalcemia-inducing nondemineralizing doses of an analog of 1,25-(OH)2D3, 1 alpha,25-(OH)2-20-epi-22-oxa-24,26,27-trishomo-vitamin D (KH1060), can prevent type I diabetes. Female NOD mice received 1,25-(OH)2D3 (5 micrograms/kg), KH1060 (0.4 or 0.2 micrograms/kg), or the treatment vehicle ip every 2 days from 21-200 days of age. The incidence of diabetes in controls was 17 of 31 (55%), whereas 7 of 38 (18%) 1,25-(OH)2D3-treated mice, 3 of 27 (11%) KH1060 (0.4 micrograms/kg)-treated mice, and 6 of 27 (22%) KH1060 (0.2 micrograms/kg)-treated mice developed diabetes (P < 0.025 vs. controls). Protection was achieved with the low KH1060 dose without effects on calcium or bone metabolism, as evaluated by serum calcium (9.5 +/- 0.4 vs. 9.4 +/- 0.3 mg/dl in controls; P = NS), serum osteocalcin (82 +/- 17 vs. 83 +/- 20 ng/ml; P = NS), bone calcium content (6.8 +/- 0.7 vs. 6.4 +/- 0.5 mg/tibia; P = NS), urinary calcium (21 +/- 4 vs. 21 +/- 4 mg/dl; P = NS), pyridinoline excretion, and duodenal calbindin-D9K concentration. The proposed mechanism of action is a restoration of suppressor cell activity, as demonstrated in vitro (suppressor cell assay) and in vivo (cell transfer experiments). This study demonstrates that an analog of 1,25-(OH)2D3 prevents type I diabetes in NOD mice without significant effects on calcium or bone metabolism.

Animals↗
PubMed1995

[Immune modulation by vitamin D analogs in the prevention of autoimmune diseases].

Vitamin D has been discovered at the beginning of this century. 7-Dehydrocholesterol is converted to vitamin D3 in the skin and after several hydroxylations it is further converted to the active hormonal form, 1 alpha,25-(OH)2D3. Vitamin D stimulates the absorption of calcium and phosphate and is an essential link in bone resorption and formation and calcium metabolism. 1 alpha,25-(OH)2D3 acts through a vitamin D receptor. These receptors are not only present in clinical target organs (kidney, gut, liver) but can also be found in a wide variety of "non-classical" tissues (keratinocytes, cells belonging to the immune system). Moreover, numerous cells (keratinocytes, macrophages) can locally synthetize or can be induced to synthetize 1 alpha,25-(OH)2D3 and these cells are responsive to its action. When these data are combined, a possible paracrine function of 1 alpha,25-(OH)2D3 can be suspected. Via this paracrine function 1 alpha,25-(OH)2D3 can suppress the cellular and humoral immunity. Based on the discovery of these effects on immune cells in vitro it became clear that 1 alpha,25-(OH)2D3 might be an interesting molecule to prevent autoimmune diseases and organ transplantation. This has already been shown in several animal models (Heymann nephritis, diabetes mellitus, experimental allergic-encephalomyelitis, lupus). 1 alpha,25-(OH)2D3 demonstrates however some side-effects (hypercalciuria, hypercalcemia, bone resorption) and for this reason 1 alpha,25-(OH)2D3-analogs are developed with dissociated effects i.e. an activity profile that allows a specific action on non-classical tissues without calcemic effects. Some chemical modifications of the side chain, A and/or CD-ring results in "superanalogs" with 10 to 100-fold more activity on cell differentiation and the immune system then 1 alpha,25-(OH)2D3 but with less calcemic activity in vivo. These biological effects can be explained by differences in pharmacokinetics (low affinity for the plasma vitamin D-binding protein and short extracellular half-life) and increased intracellular activation and gen transactivation. Preclinical research must still be done to select the most potent superanalogs and to find the exact protocols for the prevention and treatment of autoimmune diseases and rejection of transplanted organs.

Animals↗
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↗
PubMed1995

A single-center multiple regression analysis of covariates associated with long-term cadaveric renal allograft survival: further improvement of long-term results with CsA.

This single center analysis shows further improvement in the already excellent long-term, cadaveric renal allograft survival with Aza since the introduction of CsA. In contrast to the findings from the UCLA/UNOS multicenter registries, these results support other observations that the type of maintenance immunosuppression does indeed influence the long-term attrition rate of cadaveric, renal allografts.

Adult↗
PubMed1994

Spontaneous reestablishment of self-tolerance in BB/Pfd rats.

We describe a substrain of BB rats, BB/Pfd, characterized by a loss of autoimmune potential soon after onset of diabetes. When fresh syngeneic (BB/Pfd) islets (6 islets/g body weight) were transplanted under the kidney capsule of diabetic BB/Pfd rats 1-2 weeks after diabetes onset (n = 14), no recurrence of diabetes occurred. When, however, islets were transplanted on the day of diabetes diagnosis (n = 16), 10 animals were able to destroy the transplant (P < 0.005 vs. previous group). Pancreatic biopsies taken at the moment of transplantation in both groups showed an almost complete disappearance of beta cells and also insulitis in the pancreata of the 1- to 2-week diabetic rats, while the acutely diabetic rats still conserved a certain amount of beta cells and a florid insulitis. The development of a general immune defect was not the cause of this nonrecurrence, since allogeneic islet grafts were easily rejected (7 of 8), nor was there a general defect in mounting immune memory, since second set skin grafts could be rejected in an accelerated manner (9.7 vs. 15.8 days). The development of suppressor mechanisms as cause for nonrecurrence could not be demonstrated, since transfer of lymphocytes taken from 1- to 2-week diabetic rats into acutely diabetic rats at the moment of syngeneic islet transplantation was unable to prevent recurrence of disease (6 recurrences in 10 animals). We conclude that in the BB/Pfd substrain, the autoimmune capacity wanes rapidly after the onset of diabetes. This loss of autoimmune potential is parallelled by a disappearance of insulitis in the native pancreas, but the exact mechanisms of the spontaneous reestablishment of self-tolerance remain unclear.

Animals↗
PubMed1994

Prevention of autoimmune diabetes in NOD mice by 1,25 dihydroxyvitamin D3.

1,25 dihydroxyvitamin D3, the active form of vitamin D, has immunomodulatory properties in vitro and in vivo. We report that treatment with 1,25 dihydroxyvitamin D3 (5 micrograms/kg on alternate days) prevents the development of clinical diabetes in NOD mice, an animal model of human autoimmune diabetes. Diabetes incidence in female NOD mice at the age of 200 days was reduced to 8% in the 1,25 dihydroxyvitamin D treated group vs 56% in the control group (p < 0.0001). In parallel, treatment with 1,25 dihydroxy-vitamin D3 resulted in a complete normalisation of the capacity to induce suppressor mechanisms in an autologous MLR, which is severely depressed in control NOD mice. The existence of such suppressor cells was confirmed in transfer experiments, whereby cotransfer of splenocytes from 1,25 dihydroxyvitamin D3 treated NOD mice prevented diabetes transfer by splenocytes from diabetic NOD mice into irradiated, 6-8-week-old male NOD mice. Other known immune defects of the NOD mice, such as defective natural killer cell killing of YAC-1 targets and defective thymocyte activation by anti-CD3 were not corrected. The pharmacological doses of 1,25 dihydroxyvitamin D3 were universally well tolerated as reflected by a normal weight gain of the mice. Serum calcium was increased (2.5 +/- 0.2 vs 2.2 +/- 0.2 mmol/l in the control group, p < 0.005), whereas osteocalcin levels nearly doubled and bone calcium content was halved. These findings show that 1,25 dihydroxyvitamin D3 can prevent diabetes in NOD mice, probably through the correction of their defective suppressor function.

Animals↗
PubMed1994

A prospective, randomized trial of pretransplant blood transfusions in cadaver kidney transplant candidates. Leuven Collaborative Group for Transplantation.

To assess the effect of pretransplant blood transfusions on the outcome of cadaveric kidney transplantation, a single-centre analysis was performed of 171 patients randomly assigned to receive no pretransplant transfusion (n = 85) or to receive at least three random blood transfusions (n = 86). After transfusion 18 of the latter patients developed circulating lymphocytotoxic T-cell antibodies, but the sensitization was only transient. At the time of transplantation, none was still sensitized. In both groups 60 patients have been transplanted. Patient and graft survival rates were significantly higher in the transfused group than in the non-transfused group. In the non-transfused patients the higher mortality was due to complications related to repeated anti-rejection therapy. Non-transfused patients had more repeated acute rejection episodes than the transfused patients. The present study indicates that pretransplant blood transfusions still facilitate graft acceptance even in the setting of good HLA matching and with cyclosporine as the basic immunosuppressant. The risk of sensitization is very low.

Adult↗