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T Diamantstein

Publications and source records attributed to T Diamantstein.

At least 73 records · Page 4Linked to original sources
PubMed1990

The mechanism of synergistic interaction between anti-interleukin 2 receptor monoclonal antibody and cyclosporine therapy in rat recipients of organ allografts.

Untreated anephric LEW rats die ca. 9 days following transplantation of LBNF1 kidney allografts. Although treatment with ART-18, a mouse antirat IL-2R mAb (300 micrograms/kg/day x 10 days), prolonged graft survival to ca. 3 weeks, the severely impaired renal function was comparable to untreated controls (creatinine levels 3-5 mg/dl). In contrast, simultaneous infusion of ART-18 and a very low dose of CsA (0.75 mg/kg x 10 days), marginally effective on its own, resulted in survival of greater than 45 days; the grafts exhibited relatively good function comparable to that in rats treated with full-dose (15 mg/kg/day) CsA. This beneficial biological effect did not depend upon elevated CsA trough levels in animals conditioned with both modalities. The CD4:CD8 ratio at the graft site was lowest (0.3-0.4) in recipients treated with ART-18 + CsA. Synergy between the two agents has been demonstrated by adoptive transfer studies in which nonspecific suppression has been conferred selectively by cells infiltrating kidney grafts in rats given ART-18 and CsA in concert but not separately (LBNF1 and WF test cardiac allograft survival ca. 12 days). In contrast, suppression in the recipient spleens was donor-specific; both CD4 and CD8 cells prolonged test graft survival. Immunohistological evaluation of renal allografts revealed that therapy with ART-18 or low-dose CsA alone failed to deplete IL-2R+ cells and prevent production of IL-2, IFN-g, and TNF. In contrast, the frequency of infiltrating IL-2R+ cells and elaboration of endogenous cytokines in non-uremic hosts receiving combination therapy was greatly depressed, stressing again synergistic interaction between ART-18 and CsA. Additionally, markedly reduced class II antigen induction, XL-fibrin deposition, and glomerulitis may also contribute to prolonged survival and satisfactory function of kidney allografts in this animal group.

Animals↗
PubMed1990

Serum levels of soluble CD30 molecule (Ki-1 antigen) in Hodgkin's disease: relationship with disease activity and clinical stage.

In all cases of Hodgkin's disease (HD) Reed-Sternberg (RS) cells express the CD30 antigen. It has been recently demonstrated that this molecule can be released from the cell membrane of CD30+ neoplastic cells in a soluble form (sCD30), detectable in culture supernatants and body fluids. In this paper we investigated by an immunoassay the serum levels of sCD30 in 58 patients with HD, in order to define the possible relationship of this molecule to the clinical and pathological findings. sCD30 molecule was found at detectable levels in 24 out of 50 patients (48%) with active disease, whereas it was always absent in control sera and in cases in complete remission. Among the patients with active HD, the incidence and mean values of detectable levels (+/- SEM) of sCD30 were higher in cases with progressive or relapsing disease (61.5%, mean 458 +/- 190 U/ml) as compared to those at presentation (43.2%, mean 116 +/- 33 U/ml). Among the cases at presentation, detectable levels were observed more often in patients with advanced stages (III + IV: 61%) and constitutional symptoms ('B': 61.5%) than in early stages (I + II: 26%) and without symptoms ('A': 33.3%). In addition, higher mean values were found in stages III + IV (182 +/- 60 U/ml) and in 'B' cases (208 +/- 73 U/ml) than in stages I + II (65 +/- 30 U/ml) or 'A' patients (64 +/- 26 U/ml). The above findings suggest a possible role for the sCD30 as a tumour marker in HD.

Adolescent↗
PubMed1990

Increased serum levels of soluble IL-2 receptor, CD30 and CD8 molecules, and gamma-interferon in angioimmunoblastic lymphadenopathy: possible pathogenetic role of immunoactivation mechanisms.

Abnormal immunoreaction associated with increased cell activation phenomena might play a role in the pathogenetic events leading to the development of angioimmunoblastic lymphadenopathy (AILD). In the present study we investigated the serum levels of some soluble molecules related to cell activation in 24 patients with AILD at presentation. In particular, we measured by immunoenzymatic or immunoradiometric techniques the levels of the Tac peptide (sIL-2R), soluble CD30 (sCD30) and CD8 (sCD8) antigens, and gamma-IFN (gIFN). The results show that all the above molecules are increased as compared to normal controls, with a different pattern of increase for the different molecules. The sIL-2R levels were very high in all cases with no overlap between AILD and control samples (mean 6315 +/- 3374 U/ml, controls 271 +/- 112 U/ml, P less than 0.001). Very high values of the sCD30 antigen (722 +/- 895 U/ml) were detected in all cases but five, as opposed to the lack of detectable levels in controls. A significant increase of sCD8 (978 +/- 646 U/ml, controls 334 +/- 95 U/ml, P less than 0.01) and gIFN (329 +/- 236 U/ml, controls 97 +/- 43 U/ml, P less than 0.01) was also observed with some overlap between AILD samples and controls. The above findings further support the view that a condition of abnormally enhanced cell activation is likely to play a central role in the pathogenetic events leading to the composite clinicopathological picture of AILD.

Antigens, CD↗
PubMed1990

Soluble interleukin 2 receptor and tissue polypeptide antigen serum concentrations in end-stage renal failure.

Serum concentrations of soluble interleukin 2 receptor (IL-2R) were measured in 65 hemodialysis patients and compared with serum levels of beta 2-microglobulin and tissue polypeptide antigen (TPA). Elevated IL-2R levels, found in 85% of examined patients, correlated with elevated TPA serum concentrations (p less than 0.05). Patients with high IL-2R levels were significantly younger (p less than 0.05) than patients with low levels. Primary renal disease and residual renal function had no significant influence on TPA or IL-2R serum concentrations. In 16 patients with carpal tunnel syndrome, increased serum concentrations of IL-2R (p less than 0.005) and TPA (p less than 0.001) were found. We conclude that a non-specific dialysis-induced activation of epithelial and lymphoid cells rather than a specific immune response could explain the concomitant elevation of IL-2R and TPA serum concentrations in hemodialyzed patients. Patients with pronounced cell turnover, reflected by elevated IL-2R and TPA levels, may show an increased susceptibility to dialysis-associated amyloidosis.

Aged↗
PubMed1990

Tumor necrosis factor alpha and lymphotoxin production in Hodgkin's disease.

It is likely that the characteristic histologic features of Hodgkin's disease reflect cytokine production by the tumor cell population. Tumor necrosis factor alpha (TNF-alpha) and lymphotoxin (tumor necrosis factor beta [TNF-beta]) are important inflammatory mediators with wide-ranging effects within the lymphoreticular system. The aim of the present study was to investigate TNF-alpha and lymphotoxin production in the Hodgkin's disease-derived cell lines L428 and L540. At the product level, both cytokines could be demonstrated by immunostaining with specific monoclonal antibodies. TNF-alpha could be demonstrated by means of an enzyme-linked immunosorbent assay in culture supernatants from both cell lines as well as in cell lysates of L428 and L540 cells. Cytotoxic activity could be achieved only in L428 supernatants. This cytotoxic activity could not be blocked by the addition of a polyclonal antibody against TNF-alpha, but was partially inhibited with the monoclonal antibody against lymphotoxin. Synthesis of TNF-alpha and lymphotoxin in both L428 and L540 was confirmed by demonstrating the intracellular-specific messenger RNA (mRNA) using specific cDNA clones in Northern blot analysis. In situ hybridization studies with the TNF-alpha cDNA probe gave positive hybridization signals in L428 and in L540. These results demonstrate the transcription, translation, and export of TNF-alpha and lymphotoxin in cultured Hodgkin's disease-derived cell lines. In addition, results of preliminary experiments are presented in which we demonstrate Reed-Sternberg cells positive for TNF-alpha protein and mRNA in different Hodgkin's disease tissue biopsies, indicating that, at least for TNF-alpha, our cell line data are relevant to the neoplastic population present in Hodgkin's disease tissue.

Biopsy↗
PubMed1989

Mechanism of action of anti-IL-2R monoclonal antibodies. ART-18 prolongs cardiac allograft survival in rats by elimination of IL-2R+ mononuclear cells.

ART-18, a mouse IgG1 mAb recognizing the IL-2 binding domain of the rat p55 subunit IL-2R molecule, prevents graft rejection in various experimental models, although its mechanism of action in vivo, like that of anti-IL-2R mAb generally, remains elusive. These studies were designed to define whether IL-2R+ T effector cells were actually eliminated or their function merely inhibited by comparing directly the in vitro and in vivo efficacy of intact ART-18 and its F(ab)/F(ab')2 fragments. Addition of each mAb preparation profoundly suppressed MLR set up between naive LEW responders and x-radiated BN stimulators, suggesting that mAb fragments retained Ag binding functions in vitro. However, both ART-18 F(ab) and F(ab')2 were ineffectual in vivo as judged by their inability to affect acute (8 days) rejection of (LEW X BN)F1 cardiac allografts in LEW recipients (graft survival ca. 11 and 9 days, respectively, compared to ca. 21 days after therapy with intact ART-18, p less than 0.001). The sera levels of ART-18 and ART-18 F(ab')2 were 4 to 5 micrograms/ml, but only less than 0.5 micrograms/ml of F(ab) could be detected. The therapeutic failure of ART-18 fragments was unrelated to potential host sensitization, as rat antimouse F(ab) or F(ab')2 serum IgG titers remained in the same range as those against intact ART-18. The role of the Fc portion of Ig in the mode of action of ART-18 was then tested further by flow microfluorimetry analysis of host mononuclear spleen cells and immunoperoxidase stains of the graft infiltrate. IL-2R+ cells were abundant in rats treated with ART-18 fragments, comparable to acutely rejecting controls. In contrast, IL-2R expression was abolished in animals undergoing ART-18 therapy. The elimination of IL-2R+ cells is required to prolong cardiac allograft survival in rats after IL-2R targeted treatment with ART-18 mAb.

Animals↗
PubMed1989

Biodistribution of anti-interleukin 2 receptor monoclonal antibodies correlates with their therapeutic efficacy following transplantation.

IL-2R-targeted therapy prevents graft rejection in various experimental models and in man. However, the principles of optimal mAb selection remain elusive, as their efficacy in vivo does not always correlate with their characteristics in vitro. ART-18 and OX-39, mouse IgG1 mAbs, define distinct epitopes on the p55 subunit of the rat IL-2R. Treatment of LEW hosts with ART-18 prolongs survival of LBN cardiac allografts up to a month; in contrast, OX-39 never affects acute (8-day) rejection. In this study, we evaluated the biodistribution of 125I-labeled ART-18 and OX-39 administered iv to untreated and heart-grafted rats. ART-18 was cleared from the circulation (half-life time ca. 29 hr) and accumulated in host lymph nodes and spleen to a greater extent than OX-39 (P less than 0.001). In contrast, OX-39 was retained in blood (half-life time ca. 66 hr) and was eventually sequestered in liver, lungs, and kidneys, a pattern comparable to an irrelevant IgG1 (MOPC-21). ART-18 but not OX-39 entered specifically acutely rejecting allografts (allograft:native heart activity ratio = 4.0 and 2.3, respectively, P less than 0.01). The distribution of ART-18 was IL-2R epitope but not mAb isotype specific as tissue accumulation of "hot" ART-18 was comparable in recipients conditioned with "cold" ART-18 of IgG1 or IgG2b isotype, but not in those treated with OX-39. Thus: (1) the biodistribution of anti-IL-2R mAbs is not random; the mAb "effective" in combating rejection (ART-18) penetrates preferentially host lymphoid tissues and the graft itself, whereas the biologically "ineffectual" mAb (OX-39) is retained in the circulation for prolonged periods; (ii) the epitope of IL-2R defined by the mAb is critical; a mAb may be "captured" by unrelated cells expressing a common epitope in vivo before reaching the related targets, and/or some epitopes may be more accessible than others for iv administered mAbs.

Animals↗
PubMed1989

Analysis of restriction fragment length polymorphism in lymphokine genes of normal and autoimmune mice.

Analysis of RFLP has been employed in lymphokine genes of autoimmune and normal mice. No polymorphism could be detected in the loci containing IL-2, IL-2 receptor, IL-5, and IFN-gamma in NZB, NZW, BxSB, and MRL/lpr mice when compared with normal mice. Allelic forms were identified in the IL-1 alpha gene of BALB/c and in the IL-4 gene of NZW. The frequency of the Bam HI RFLP in the TNF-alpha gene of NZW which has been proposed to be associated with the development of autoimmune disease in (NZB x NZW)F1 mice has been analyzed in a number of different inbred strains and in wild mice. Since the same allele is inherited in most autoimmune, healthy laboratory and wild mice the TNF-alpha gene does not seem to be one of the causal agents that contributes to the development of autoimmunity in (NZB x NZW)F1 mice.

Animals↗
PubMed1989

Suppression of P2-T cell line-mediated experimental autoimmune neuritis by interleukin-2 receptor targeted monoclonal antibody ART 18.

The monoclonal antibody ART 18 directed to the rat interleukin-2 receptor (IL-2 R) was administered to Lewis rats immediately prior to and/or on consecutive days after adoptive transfer of autoreactive P2-T line lymphocytes. The effects of ART 18 and sham treatment on the development of adoptive transfer--experimental autoimmune neuritis (AT-EAN) were assessed by clinical inspection, serial electrophysiological monitoring, and semiquantitative histomorphological analysis. Early injection of ART 18 suppressed AT-EAN while treatment after appearance of clinical signs did not. Since the IL-2 R is expressed exclusively on proliferating T cells activated by antigen, the in vivo application of an IL-2 R-targeted monoclonal antibody allows for more selective immunosuppression of experimental autoimmune disease of the peripheral nervous system than has previously been achieved.

Animals↗
PubMed1989

Ki-1 (CD30) antigen is released by Ki-1-positive tumor cells in vitro and in vivo. I. Partial characterization of soluble Ki-1 antigen and detection of the antigen in cell culture supernatants and in serum by an enzyme-linked immunosorbent assay.

An enzyme-linked immunosorbent assay (ELISA) has been developed that allows the quantitative determination of the Ki-1 (CD30) antigen in soluble form. Similar levels of sensitivity of this new Ki-1 ELISA and the ELISA previously described for measuring the soluble 55-kDa chain of the interleukin 2 receptor were seen. As assessed with this ELISA, the investigated Ki-1+ permanent cell lines released the Ki-1 antigen into the culture supernatant. In culture supernatants of concanavalin A-activated human peripheral blood lymphocytes, however, this antigen could not be detected. The released Ki-1 antigen has an apparent molecular weight (Mr) of 85,000, whereas the cell-associated Ki-1 antigen has an Mr of 105,000. We investigated sera from 30 normal donors, 15 patients with systemic infections, and 63 patients suffering from lymphomas for soluble Ki-1 antigen. In all sera from normal donors and patients with systemic infectious diseases, soluble Ki-1 antigen was below the detection limit (i.e., less than 70 pg). In contrast, high amounts of the soluble Ki-1 antigen were found in sera from 18 malignant lymphomas containing Ki-1+ tumor cells. This finding demonstrates that the release of the Ki-1 antigen takes place not only in vitro, but in vivo as well. Moreover, these results imply that the Ki-1 antigen may be used as a serum tumor marker.

Adult↗
PubMed1989

Developmentally regulated expression of the neural cell adhesion molecule (NCAM) by mouse thymocytes.

The expression of the neural cell adhesion molecule (NCAM) has been investigated during thymus ontogeny. NCAM mRNA was readily detectable at day 19 of gestation, the youngest age studied. Its level declined after birth to become undetectable at 3 weeks of age. Cell surface expression of NCAM protein was detected on 14% of day 15 fetal thymocytes and peaked during the perinatal period, when around 40% of the thymocytes expressed low to medium levels of NCAM. At postnatal day 2, the vast majority of the NCAM+ cells were also CD4+ and CD8+. At embryonic day 15, NCAM appeared also to be expressed by CD4- thymocytes since 14% of the cells were already NCAM+ whereas CD4 was virtually undetectable. In frozen section of the newborn thymus, surface staining for NCAM was present on a subpopulation of cells in the cortex, rare in the medulla and absent from the sub-capsular area. In conjunction with other cell adhesion molecules, NCAM could play a role in cell interactions during thymic development.

Age Factors↗
PubMed1989

The intermediate-affinity interleukin (IL)2 receptor expressed on Theileria annulata-infected cells comprises a single IL 2-binding protein. Partial characterization of bovine IL2 receptors.

Bovine high-, intermediate- and low-affinity interleukin 2 receptors (IL2R) were studied by ligand binding and affinity labeling using 125I-labeled IL2 and homobifunctional chemical cross-linking reagents. High- (Kd = 17 pM) and low-affinity (Kd greater than 6 nM) IL 2R were detected on concanavalin A-activated peripheral blood lymphocytes (PBL). Theileria annulata (TA)-infected autonomously growing PBL (TA-PBL) express predominantly intermediate-affinity IL2R (Kd = 1 nM). Affinity-labeling studies revealed that the high-affinity IL2R comprises a 55-kDa (L chain) and an additional 90-kDa IL 2-binding protein (H chain). TA-PBL express predominantly the H chain. In contrast to the human chain, the bovine form was not separable by sodium dodecyl sulfate-polyacrylamide gel electrophoresis/urea into the two distinct bands H1 and H2 and ran in parallel to the human H2 band. These results suggest (a) that the bovine intermediate-affinity IL2R comprises a single H chain and (b) that the single H chain and the L chain are sufficient to form the functional high-affinity bovine IL2R.

Affinity Labels↗
PubMed1989

Structure and evolution of mouse interleukin 6 gene.

Restriction fragment length polymorphism in the interleukin 6 gene of murine rodents extending phylogenetically from Mus musculus domesticus to the rat has been analyzed. Most species exhibit distinct restriction site patterns. In contrast, limited polymorphism was found in the tumor necrosis factor alpha gene indicating different selective pressure acting on both genes. The gene encoding interleukin 6 was isolated from a genomic library and the exon/intron organization was determined by restriction analysis and limited DNA sequence analysis. It consists of five exons which distribute over about seven kilobases, thus resembling in structure and organization the human counterpart. Furthermore, no restriction fragment length polymorphisms in the interleukin 6 gene of autoimmune strains NZB, NZW, MRL-lpr/lpr and BxSB could be detected for either EcoRI, BamHI or HindIII.

Animals↗
PubMed1989

Interaction between C3 and IL-2; inhibition of C3b binding to CR1 by IL-2.

We previously reported that C3 has a role in the enhancement of the IL-2 dependent proliferation of helper T cells. Because the IL-2R has a structural homology with the complement proteins, such as CR1 and CR2, we studied the possible ligand crossreactions on CR1 and IL-2-receptor, and the direct interaction between C3 and IL-2. While C3 has an enhancing effect on the IL-2 dependent proliferation of HT-2, a CR1-positive mouse T-cell line, the growth of the CTLL-16 line (CR1-negative) is not affected by C3. It has been proven that neither the insolubilized C3 nor the soluble C3b-like C3 react with the IL-2 binding epitope of the IL-2 receptor. However, using human RBC we have demonstrated that the binding of aggregated C3 to CR1 is inhibited by rIL-2, in a dose-dependent manner. When RBC were incubated with rIL-2 and FITC-labelled Fab-anti-CR1 simultaneously, there was no inhibition in the fluorescence intensity. As detected by ELISA, rIL-2 was bound to the same extent by insolubilized C3, C3b, and C3c, while C3d coat had lower binding capacity. The receptor-binding epitope of IL-2 is intact in the complex of complement proteins and rIL-2, as demonstrated by the binding of DMS1, a monoclonal antibody reacting with the receptor site of IL-2. It is strongly suggested that C3b may play a role in the growth of CR1 positive T cells.

Cell Line↗
PubMed1989

Studies on the formation of high-affinity IL-2 binding sites of an IL-2 receptor p55 + p75 heterodimeric complex: functional importance of a determinant on the p55 subunit defined by a monoclonal antibody AHT-107.

The monoclonal antibody (mAb) AHT-107 recognized a determinant distal to the interleukin 2 (IL-2) binding site on the p55 subunit of the IL-2 receptor (IL-2R) (the Tac antigen, CD25) of human T lymphoblasts, while the mAb AHT-54 recognized a determinant close to the IL-2 binding site as did the anti-Tac. The AHT-107 inhibited IL-2 dependent proliferation of human T lymphoblasts equally as well as did the AHT-54. Both mAbs inhibited the high-affinity binding and crosslinking of IL-2 to the p55 + p75 heterodimeric complex on forskolin-treated YT cells. Remarkably, the AHT-107 did not inhibit the low-affinity binding and cross-linking of IL-2 to the p55 molecule on human p55 cDNA-transfected cells, while the AHT-54 as well as anti-Tac did so. In contrast, the mAb PC61, that was previously reported to recognize a determinant distal to the IL-2 binding site on the mouse p55 subunit of IL-2R and to dissociate IL-2 from the high-affinity IL-2R complex by altering the conformation of the p55 molecule itself, inhibited the low-affinity binding and cross-linking of IL-2 to the p55 molecule on mouse p55 cDNA-transfected cells. Further, we showed that the AHT-107 did not dissociate IL-2 from the high-affinity IL-2R complex once formed on human T lymphoblasts.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗