Search PubMed⌕ Search

Biomedical subjects

D Abramowicz

Publications and source records attributed to D Abramowicz.

At least 73 records · Page 4Linked to original sources
PubMed1995

Hypercalcaemia complicating systemic oxalosis in primary hyperoxaluria type 1.

Persistent hypercalcaemia was observed in two patients with oxalate osteopathy complicating primary hyperoxaluria type 1; four other cases have been reported in the literature. In none of the six patients could hypercalcaemia be ascribed to hyper-parathyroidism secondary to renal failure. It occurred in the absence of aluminum intoxication, and was associated with normal calcitriol. Hypercalcaemia responded to mithramycin in one patient, and to corticosteroid administration in three; corticosteroid withdrawal was followed by recurrence of hypercalcaemia in the three cases. It is suggested that hypercalcaemia results from the osteoclast-stimulating activity of macrophages constituting the granulomata which invade the bone marrow in response to oxalate deposition. Whatever its pathogenesis, a trial of corticosteroid appears warranted for treating hypercalcaemia complicating oxalosis.

Adrenal Cortex Hormones↗
PubMed1994

Systemic release and protective role of IL-10 in staphylococcal enterotoxin B-induced shock in mice.

Staphylococcal enterotoxin B (SEB) is a bacterial superantigen that induces the production of several pro-inflammatory cytokines, leading to a self-limited shock. In the present study, we show that SEB also triggers the systemic release of IL-10, an anti-inflammatory and immunosuppressive cytokine. Serum IL-10 was undetectable (< 1000 pg/ml) in control BALB/c mice and rose to 8500 +/- 2850 pg/ml (mean +/- SEM) 4 h after injection of 100 micrograms SEB. Cell depletion experiments and analysis of IL-10 mRNA expression indicated that CD4+ cells played a major role in SEB-induced IL-10 production. Pretreatment of mice with neutralizing anti-IL-10 mAb before SEB challenge did not modify the release of TNF but led to increased and sustained IL-2 and IFN-gamma serum levels. Furthermore, although no lethality occurred in mice injected with SEB and control mAb, injection of anti-IL-10 mAb before SEB resulted in a 30% lethality (p < 0.05). This lethality was completely prevented by anti-IFN-gamma mAb injection, indicating that IFN-gamma plays a crucial role in the increased toxicity of SEB in anti-IL-10 mAb-injected mice. We conclude that SEB induces the production of IL-10 by CD4+ cells in vivo and that endogenous IL-10 plays an important immunoregulatory role in this model by down-regulating IL-2 and IFN-gamma production.

Animals↗
PubMed1994

IFN-gamma prevents Th2 cell-mediated pathology after neonatal injection of semiallogenic spleen cells in mice.

BALB/c mice injected at birth with 10(8) (A/J X BALB/c)F1 hybrid spleen cells develop an autoimmune host-vs-graft (HVG) disease as a result of activation of donor B cells by host CD4+ cells. The antidonor CD4+ cells seem to be Th2-like cells, inasmuch as they are profoundly deficient in IL-2 and IFN-gamma production, but secrete high levels of IL-4 and IL-10. As IFN-gamma is known to inhibit the development of TH2 cells, we attempted to modulate HVG disease by injecting rIFN-gamma. First, we found that 10 micrograms of rIFN-gamma given on days 1 and 3 after birth reduced the serum hyper-IgE of HVG mice by 90% and the serum hyper-IgG1, by 70%. In addition, rIFN-gamma administration significantly decreased the anti-DNA IgG1 titers and prevented the occurrence of anti-glomerular basement membrane and anti-laminin IgG1 Abs as well as the formation of immune deposits in renal glomeruli. These effects were not caused by the abrogation of chimerism, as indicated by the persistence of donor-type B cells in lymph nodes and of Igs bearing donor allotype in serum. MLC experiments indicated that the major effect of early rIFN-gamma administration was to restore the production of IL-2 and IFN-gamma by donor-specific T cells while these cells still secreted significant amounts of IL-4 and IL-10. Unresponsiveness of antidonor cytolytic T cells was not influenced by rIFN-gamma. We conclude that rIFN-gamma prevents the TH2-type response induced by the neonatal injection of semiallogeneic spleen cells and the associated pathology.

Animals↗
PubMed1994

In vivo T cell activation by anti-CD3 monoclonal antibody induces soluble TNF receptor release in mice. Effects of pentoxifylline, methylprednisolone, anti-TNF, and anti-IFN-gamma antibodies.

Injection of anti-CD3 is accompanied by an increase in systemic TNF, a mediator of the physiologic changes induced by anti-CD3 injection. Various mechanisms have been reported to be responsible for TNF inactivation and clearance. Recently, it has become evident that circulating soluble TNFRs (P55 and P75), which are known to increase in response to TNF inducers such as LPS, represent a natural protection mechanism against circulating TNF. Here we show that triggering the TCR by anti-CD3 injection results in a strong induction of both systemic TNF and soluble TNFR release. Maximal levels of TNF were reached after 2 h (10 ng/ml). Maximum levels of P55 (450 pg/ml) were reached between 0.5 and 8 h, whereas the highest levels of P75 were reached after 2 h (28 ng/ml). Because TNF and IFN-gamma are supposed to be involved in the pathophysiology of the anti-CD3 response, we investigated the influence of in vivo neutralization of TNF and IFN-gamma. Injection of mAb to TNF and IFN-gamma significantly reduced systemic TNF levels and both soluble TNFR levels. Two inhibitors of anti-CD3 induced TNF release; steroids and pentoxifylline both reduced TNF levels and P75 levels without affecting P55 levels. The results show that T cell activation induces both systemic TNF release and release of both soluble TNFRs. Although TNF and IFN-gamma are involved in this mechanism, their role does not seem to be crucial.

Animals↗
PubMed1994

Modulation of the release of cytokines and reduction of the shock syndrome induced by anti-CD3 monoclonal antibody in mice by interleukin-10.

Since IL-10 was recently shown to inhibit several T cell functions in vitro, we investigated the effects of IL-10 on the cytokine release syndrome induced in mice by the 145-2C11 anti-CD3 mAb. As OKT3 in man, this mAb induces a massive polyclonal T cell activation before to induce immunosuppression. First, we found that administration of 1000 U of recombinant mouse IL-10 (mIL-10) 30 min before injection of 10 micrograms of the 145-2C11 antimouse CD3 mAb markedly reduced the systemic release of IFN-gamma and TNF. In contrast, IL-10 pretreatment did not significantly modify the release of IL-6. To determine the effect of IL-10 pretreatment on the endogenous secretion of IL-10 induced by the 145-2C11 mAb, mice were injected with human IL-10 (hIL-10) which does not cross-react in the ELISA for mIL-10 determination. While hIL-10 was as efficient as mIL-10 in reducing TNF and IFN-gamma release, it did not modify peak serum levels of IL-10. The modulation of cytokine production by mIL-10 was associated with a significant reduction of the toxicity of the 145-2C11 mAb, as assessed by the attenuation of hypothermia and by the reduced lethality in D-galactosamine-sensitize mice. We conclude that IL-10 differentially regulates the in vivo production of cytokines and decreases the systemic toxicity induced by the 145-2C11 mAb. These observations suggest potential therapeutic applications of IL-10 in organ transplantation, especially in association with anti-CD3 mAb.

Animals↗
PubMed1994

[Allogenic reaction, a model of autoimmunity].

Allogenic diseases induced in rodents by the inoculation of foreign lymphocytes represent useful models to investigate the mechanisms governing the activation of autoreactive B cells in systemic lupus erythematosus and related autoimmune disorders. The role of CD4+ helper T cells recognizing foreign class II MHC molecules has been particularly well established in murine chronic graft-versus-host disease and host-versus-graft disease. The T cells involved in these models essentially produce interleukin-4 and interleukin-10, which corresponds to the phenotype of Th2 cells. The association between autoimmunity and cellular immunodeficiency in experimental allogenic diseases could therefore be directly related to the hyperactivity of Th2 cells. Similar mechanisms might be operative in human systemic autoimmune diseases as well as in other clinical settings such as graft-versus-host disease after bone marrow transplantation or the acquired immunodeficiency syndrome.

Animals↗
PubMed1994

Interleukin-10 controls interferon-gamma and tumor necrosis factor production during experimental endotoxemia.

Interleukin-10 (IL-10) is a potent inhibitor of lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF) production and has been shown to protect mice from endotoxin shock. As IFN-gamma is another important mediator of LPS toxicity, we studied the effects of IL-10 on LPS-induced IFN-gamma synthesis in vitro and in vivo. First, we found that the addition of recombinant human IL-10 (rhIL-10) (10 U/ml) to human whole blood markedly suppressed LPS-induced IFN-gamma release while neutralization of endogenously synthesized IL-10 resulted in increased IFN-gamma levels. The ability of rIL-10 to inhibit LPS-induced IFN-gamma synthesis was also observed in vivo in mice. Indeed, administration of 1000 U recombinant mouse IL-10 (rmIL-10) 30 min before and 3 h after challenge of BALB/c mice with 100 micrograms LPS resulted in a threefold decrease in peak IFN-gamma serum levels. We then examined the production and the role of IL-10 during murine endotoxemia. We found that LPS injection causes the rapid release of IL-10, peak IL-10 serum levels being observed 90 min after LPS challenge. Neutralization of endogenously produced IL-10 by administration of 2 mg JES5-2A5 anti-IL-10 monoclonal antibody (mAb) 2 h before LPS challenge resulted in a marked increase in both TNF and IFN-gamma serum levels while irrelevant isotype-matched mAb had no effect. The enhanced production of inflammatory cytokines in anti-IL-10 mAb-treated mice was associated with a 60% lethality after injection of 500 micrograms LPS, while all mice pretreated with control mAb survived. We conclude that the rapid release of IL-10 during endotoxemia is a natural antiinflammatory response controlling cytokine production and LPS toxicity.

Animals↗
PubMed1994

Systemic release of interleukin-10 during orthotopic liver transplantation.

Experimental and clinical observations indicate that the liver allograft is less immunogenic than other organ transplants and can promote immune tolerance. Because interleukin-10 recently emerged as a macrophage and T-cell-derived cytokine with potent immunosuppressive properties, we studied its production in 28 patients undergoing orthotopic liver transplantation. Plasma levels of immunoreactive interleukin-10 dramatically increased within 2 hr after liver allograft reperfusion, with peak levels ranging between 214 and 4998 pg/ml (median = 677 pg/ml). This systemic release of interleukin-10 was transient because it returned to low levels by 48 hr (range = 26 to 51 pg/ml). The higher interleukin-10 levels measured in right atrial blood as compared with portal blood indicated that interleukin-10 was most likely synthesized within the liver graft. To get insight into the cellular origin of interleukin-10, we also measured serum levels of interleukin-4 and interferon-gamma, both produced by T cells, and interleukin-8, a cytokine secreted by macrophages, in eight patients. Interleukin-4 and interferon-gamma levels remained undetectable in most of the patients, whereas interleukin-8 levels paralleled those of interleukin-10. Portal endotoxemia was probably not involved in interleukin-10 production because endotoxin levels remained low (< 20 pg/ml) before and after liver allograft reperfusion. Interleukin-10 plasma levels did not correlate either with cold ischemia time or with the occurrence of rejection episodes. We conclude that orthotopic liver transplantation is associated with a massive release of interleukin-10 and interleukin-8, most likely produced by allograft macrophages.

Adult↗
PubMed1994

In vivo immunosuppression induced by a weakly mitogenic antibody to mouse CD3: evidence that induction of long-lasting in vivo unresponsiveness requires TcR signaling.

The use of anti-CD3 monoclonal antibodies (mAb) to treat allograft rejection has been complicated by the morbidity observed during the first days of treatment, secondary to T cell activation and cytokine release. Available evidence in a mouse model indicates that F(ab')2 fragments of an anti-CD3 mAb are not mitogenic in vitro and can be injected in vivo without apparent toxicity. However, their immunosuppressive capacity is dramatically reduced, suggesting that long-term immunosuppression mediated by anti-CD3 antibodies in vivo may be associated to their mitogenic capacity. This paper demonstrates that a poorly mitogenic anti-CD3 mAb is able to induce potent immunosuppression in vivo with reduced morbidity. This finding suggests that immunosuppression in vivo by anti-CD3 mAbs is not directly related to their activation properties but nevertheless requires signaling capacities. Therefore, immunosuppression in vivo may be best achieved by using antibodies able to deliver an incomplete activation signal to T cells (thus avoiding systemic cytokine release), possibly leading to anergy. The implications of this study for the development of immunosuppressive antibodies are discussed.

Animals↗
PubMed1994

OKT3 serum levels as a guide for prophylactic therapy: a pilot study in kidney transplant recipients.

The use of OKT3 as prophylaxis in renal transplantation results in a reduced incidence of graft rejection and appears to have beneficial effects on long-term kidney graft survival. However, we and others have observed that patients still experience rejection during the period of OKT3 prophylaxis given at the regular 5 mg/day dose. Many of these patients had no circulating CD3+ cells at the time of rejection, but their OKT3 serum levels were distinctly low (< 500 ng/ml). This led us to adjust OKT3 doses (5 or 10 mg) daily, according to the patients' OKT3 levels, in order to maintain an OKT3 concentration of around 1000 ng/ml. In addition, patients were randomized to receive either 5 mg (group 1, n = 15) or 10 ng (group 2, n = 14) OKT3 as the initial three doses. Concomitant immunosuppression consisted of azathioprine and steroids, with the introduction of cyclosporin A on day 11. Patient survival was 100% after 3 months of follow-up. The intensity of OKT3 first-dose reactions was similar in both groups. Intragraft thrombosis, initially observed in a previous group of patients who received a fixed 10 mg/day OKT3 prophylaxis, occurred in three patients in group 1 and resulted in two graft losses. The cumulative OKT3 dose was similar in both groups (mean +/- SEM 98 +/- 2 mg in group 1 vs 102 +/- 3 mg in group 2) and higher than the 70 mg usually administered. Group 2 patients had higher OKT3 serum levels during the first 4 days of therapy. No correlation could be found between patient weight and cumulative OKT3 dose (r = 0.29).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Tuberculosis presenting as acute hepatitis in a renal transplant recipient.

We observed a kidney transplant recipient in whom acute hepatitis was the initial manifestation of tuberculosis, preceding radiological lung involvement by several weeks. The diagnosis was suspected and treatment initiated based on the finding of a granulomatous hepatitis on liver biopsy. Mycobacterial tuberculosis was grown and identified first in liver samples and only later in sputum and bone marrow. This case illustrates the protean manifestations of tuberculosis in immunosuppressed patients.

Acute Disease↗