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Biomedical subjects

M Goldman

Publications and source records attributed to M Goldman.

At least 55 records · Page 3Linked to original sources
PubMed2001

Acute rejection in the absence of cognate recognition of allograft by T cells.

We studied the effects of the indirect pathway of allograft recognition using T cells from TCR transgenic Marilyn mice, which recognize the male Ag H-Y in an I-A(b)-restricted fashion. The T cells are not alloreactive to the H-2(k) haplotype, because they are not activated when adoptively transferred into recombinase-activating gene-2(-/-) common gamma-chain(-/-) double-mutant H-2(k) male or female mice. However, skin from H-2(k) males, but not from H-2(k) females, is acutely rejected by recombinase-activating gene-2(-/-) transgenic female recipients. In vitro, Marylin spleen cells primed by H-2(k) skin grafting proliferated and secreted both IL-4 and IFN-gamma in response to H-2(k) male stimulators. However, the removal of H-2(b) APC from the responding population abolished the response. Taken together, these results show that the indirect recognition that triggers rejection in this model is due to the recognition of H-Y Ag shed from H-2(k) male allograft and presented by the recipient's own I-A(b) APC to transgenic T cells. This study demonstrates unequivocally the capacity of naive CD4(+) T cells to promote the rejection of allografts through mechanisms that involve indirect destruction of grafted tissues.

Acute Disease↗
PubMed2001

Transfusion-transmitted malaria in Canada.

Three cases of transfusion-transmitted malaria in Canada are described. Although very rare, this diagnosis should be considered in transfusion recipients who have undiagnosed symptoms consistent with malaria. Thick and thin blood smears should be urgently examined to exclude this possibility.

Adult↗
PubMed2001

A phase 1/2 clinical trial of enzyme replacement in fabry disease: pharmacokinetic, substrate clearance, and safety studies.

Fabry disease results from deficient alpha-galactosidase A (alpha-Gal A) activity and the pathologic accumulation of the globotriaosylceramide (GL-3) and related glycosphingolipids, primarily in vascular endothelial lysosomes. Treatment is currently palliative, and affected patients generally die in their 40s or 50s. Preclinical studies of recombinant human alpha-Gal A (r-halphaGalA) infusions in knockout mice demonstrated reduction of GL-3 in tissues and plasma, providing rationale for a phase 1/2 clinical trial. Here, we report a single-center, open-label, dose-ranging study of r-halphaGalA treatment in 15 patients, each of whom received five infusions at one of five dose regimens. Intravenously administered r-halphaGalA was cleared from the circulation in a dose-dependent manner, via both saturable and non-saturable pathways. Rapid and marked reductions in plasma and tissue GL-3 were observed biochemically, histologically, and/or ultrastructurally. Clearance of plasma GL-3 was dose-dependent. In patients with pre- and posttreatment biopsies, mean GL-3 content decreased 84% in liver (n=13), was markedly reduced in kidney in four of five patients, and after five doses was modestly lowered in the endomyocardium of four of seven patients. GL-3 deposits were cleared to near normal or were markedly reduced in the vascular endothelium of liver, skin, heart, and kidney, on the basis of light- and electron-microscopic evaluation. In addition, patients reported less pain, increased ability to sweat, and improved quality-of-life measures. Infusions were well tolerated; four patients experienced mild-to-moderate reactions, suggestive of hypersensitivity, that were managed conservatively. Of 15 patients, 8 (53%) developed IgG antibodies to r-halphaGalA; however, the antibodies were not neutralizing, as indicated by unchanged pharmacokinetic values for infusions 1 and 5. This study provides the basis for a phase 3 trial of enzyme-replacement therapy for Fabry disease.

Adolescent↗
PubMed2001

Deficient IL-12(p35) gene expression by dendritic cells derived from neonatal monocytes.

To gain insight into the defects responsible for impaired Th1 responses in human newborns, we analyzed the production of cytokines by dendritic cells (DC) derived from cord blood monocytes. We observed that neonatal DC generated from adherent cord blood mononuclear cells cultured for 6 days in the presence of IL-4 and GM-CSF show a phenotype similar to adult DC generated from adherent PBMC, although they express lower levels of HLA-DR, CD80, and CD40. Measurement of cytokine levels produced by neonatal DC upon stimulation by LPS, CD40 ligation, or poly(I:C) indicated a selective defect in the synthesis of IL-12. Determination of IL-12(p40) and IL-12(p35) mRNA levels by real-time RT-PCR revealed that IL-12(p35) gene expression is highly repressed in stimulated neonatal DC whereas their IL-12(p40) gene expression is not altered. The addition of rIFN-gamma to LPS-stimulated newborn DC restored their expression of IL-12(p35) and their synthesis of IL-12 (p70) up to adult levels. Moreover, we observed that neonatal DC are less efficient than adult DC to induce IFN-gamma production by allogenic adult CD4(+) T cells. This defect was corrected by the addition of rIL-12. We conclude that neonatal DC are characterized by a severe defect in IL-12(p35) gene expression which is responsible for an impaired ability to elicit IFN-gamma production by T cells.

Adult↗
PubMed2001

Clonal Th2 cells associated with chronic hypereosinophilia: TARC-induced CCR4 down-regulation in vivo.

We analyzed the expression of chemokine receptors on clonal Th2-type CD4(+)CD3(- )lymphocytes isolated from blood of two patients with chronic hypereosinophilia. First, we observed that these Th2 cells express membrane CCR5 and CXCR4 but neither CCR3 nor CCR4 when analyzed immediately after purification. However, CCR4 appeared following culture in human serum-free medium, suggesting that it was down-regulated in vivo. Indeed, patient's serum, but not control human serum, strongly down-regulated CCR4 expression on cultured Th2 cells. As high levels of TARC, a CCR4 ligand, were detected in the serum of four hypereosinophilic patients with CD3(-)CD4(+) clonal Th2 cells, we evaluated the effect of TARC neutralization in this system. Addition of a neutralizing anti-TARC mAb inhibited CCR4 down-regulation by patient's serum, indicating that circulating TARC contributed to CCR4 down-regulation on Th2 cells in vivo. Clonal Th2 cells did not secrete high levels of TARC themselves but induced a sustained production of TARC by monocyte-derived dendritic cells, a phenomenon that was inhibited by addition of blocking mAb against IL-4 receptor. We conclude that high circulating levels of TARC in serum of patients with chronic hypereosinophilia, most likely derived from antigen-presenting cells stimulated by Th2-type cytokines, induce down-regulation of CCR4 on Th2 cells in vivo.

Adult↗
PubMed2001

Neonatal bacillus Calmette-Guérin vaccination induces adult-like IFN-gamma production by CD4+ T lymphocytes.

The immaturity of the neonatal immune system in mice is associated with defective IFN-gamma production and Th2-biased immune responses. In this study, infants vaccinated at birth with BCG produced similar concentrations of IFN-gamma in response to PPD and showed similar frequencies of IFN-gamma-producing lymphocytes as compared to immune adults. Infants and adults produced only low concentrations of IL-4 and IL-5. CD4+ T lymphocytes were the main source of IFN-gamma. Similar proportions of Th1 and Th0 PPD-specific T cell clones were observed in infants and adults. This study demonstrates that the human neonatal immune response to BCG is not biased towards Th2 and is characterized by the predominant production of IFN-gamma by CD4+ T lymphocytes.

Adolescent↗
PubMed2001

Azodicarbonamide as a new T cell immunosuppressant: synergy with cyclosporin A.

We recently demonstrated that azodicarbonamide is an immunosuppressive compound that inhibits calcium mobilization in T lymphocytes. In this study, we show that azodicarbonamide prevents the progression of human CD4+ T lymphocytes into the G1 phase of the cell cycle, inhibits their blastogenesis, down-regulates their membrane expression of CD25 and CD69, and decreases their transcription of cytokine genes. Addition of the calcium ionophore A23187 completely restores T cell proliferation in the presence of azodicarbonamide. Furthermore, azodicarbonamide synergizes with cyclosporin A to inhibit CD4+ T cell proliferation. In conclusion, the immunosuppressive action of azodicarbonamide is mainly related to its effect on the calcium mobilization machinery and is synergistic with that of calcineurin inhibitors.

Adult↗
PubMed2001

Radial-field sidebands in MAS.

The existence of sidebands at +/-v(r) in MAS spectra due to the radial component of the RF field at the edges of the coil is described theoretically and illustrated experimentally. The height of the radial-field sidebands does not depend on the spinning speed and may contribute significantly to the intensity of -1 spinning sideband of MAS modulated internal interactions for a sample placed in a rotor of length exceeding the solenoid coil or a small volume sample placed at the edge of the coil.

Journal Article↗
PubMed2001

Bacterial contamination of platelet concentrates: incidence, significance, and prevention.

Severe transfusion reactions associated with bacteria and/or their products, during or following a blood transfusion, were one of the earliest recognized complications of allogeneic blood transfusions. Bacterial contamination of blood products has thus been a problem for many decades and at present is likely the most common microbiological cause of transfusion-associated morbidity and mortality. Transfusion-associated sepsis due to contaminated platelet concentrates appears to be much more common than that due to contaminated red blood cells. The overall incidence of contaminated cellular blood products is approximately 1 in 3,000. However, transfusion to a recipient of a contaminated platelet unit may not necessarily be associated with clinically apparent morbidity, because the majority of contaminated platelet units contain relatively few organisms. In a minority of instances, contaminated units contain large numbers of potentially virulent bacteria, as well as endotoxins, and their transfusion is often associated with significant recipient morbidity and mortality. The incidence of severe septic episodes has not been clearly established, but is probably of the order of 1 per 50,000 platelet units transfused. With heightened awareness in recent years of the possibility that platelet transfusion-associated septic episodes can occur, a variety of measures have been proposed, and in some cases implemented, to try to prevent and control this transfusion risk.

Blood Platelets↗
PubMed2001

A role for eosinophils in transplant rejection.

Eosinophils release inflammatory mediators and cationic proteins that are instrumental in the pathogenesis of allergic diseases such as bronchial asthma. Here, we review experimental observations indicating that eosinophils are also involved in the rejection of allografts. We propose that their role as effectors of transplant damage becomes crucial when classical pathways of rejection are inhibited and T helper 2 (Th2) cells dominate the alloimmune response.

Animals↗
PubMed2001

Reduction of donor exposures in premature infants by the use of designated adenine-saline preserved split red blood cell packs.

OBJECTIVE: Critically ill neonates frequently require multiple small volume red blood cell (RBC) transfusions. RBC units assigned to individual infants, used sequentially in small aliquots until the original expiration date, can substantially reduce donor exposures. In 1993, adenine-saline solution (AS-3) was introduced by the Canadian Red Cross as the red cell storage medium to replace citrate-phosphate-dextrose-adenine anticoagulant-preservative solution (CPDA-1). We surveyed the safety and efficacy of using AS-3 split packs, stored up to 35 days, for premature infants. STUDY DESIGN: Units of packed cells were aseptically welded to three satellite bags using a sterile connecting device. When blood was requested for a small volume transfusion, the first satellite bag was used and the others were set aside for the same baby, for use up until their expiration date of 35 days. RESULTS: Over a 1-year period, 56 infants received a total of 263 AS-3 transfusions from 97 donors, with a mean of 4.7 transfusions and 1.7 donor exposures per infant. Following a 7-ml/kg RBC transfusion, mean rise in hematocrit (hct) was 0.04, regardless of the age of the unit, mean change in serum potassium was -0.16 mmol/l and mean change in total bilirubin was +1.86 micromol/l. The posttransfusion hct was not reduced with the use of the older red cell packs. CONCLUSION: Designated AS-3-preserved split RBC packs effectively limit donor exposures, can safely be used for neonatal small volume transfusions, and give a constant transfusion effect after up to 35 days of storage.

Adenine↗