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Biomedical subjects

H S Bresler

Publications and source records attributed to H S Bresler.

12 recordsLinked to original sources
PubMed1999

Cellular immunotherapy for patients with metastatic colorectal carcinoma using lymph node lymphocytes localized in vivo by radiolabeled monoclonal antibody.

BACKGROUND: The authors showed previously that radiolabeled monoclonal antibody (MoAb) and a hand-held, gamma-detecting probe can be used to localize tumor-reactive lymph nodes in vivo. The authors examined the feasibility, safety, and biologic effects of cellular immunotherapy using autologous cells expanded from these lymph nodes in patients with metastatic colorectal carcinoma. METHODS: Tumor-reactive lymph nodes containing radiolabeled MoAb were localized and excised from 32 patients with metastatic, unresectable colorectal carcinoma at laparotomy. Lymph nodes were dissociated, and cells were cultured ex vivo for 10-14 days. Patients received a single infusion of autologous, expanded cells with no systemic interleukin (IL)-2. RESULTS: A mean of 1.6 x 10(10) expanded autologous lymph node cells were infused with toxicity limited to occasional fevers or chills. The cells infused predominately were activated CD3+ T-cells that expressed genes for IL-4, IL-5, interferon-gamma, and granulocyte-macrophage colony stimulating factor (GM-CSF) by using reverse transcriptase-polymerase chain reaction. Indium-111 labeled cells were observed to traffic initially to the lungs, bone marrow, liver, and spleen. One patient on study achieved a partial response (>80% reduction), and mixed or minor responses were noted in 4 other patients. The responding patient's cell characteristics were notable for high levels of GM-CSF and IL-4 secretion on restimulation with immobilized anti-CD3 in vitro, and biopsies of the tumor were characterized by macrophage infiltration. The median survival of the cell-treated group compared favorably with a similar group of patients who underwent radioimmunoguided surgery without cell treatment (12.5 months vs. 5.8 months) CONCLUSIONS: The infusion of cells expanded from tumor-reactive lymph nodes localized with radiolabeled MoAb in vivo is reproducible and safe and has biologic activity, even in the absence of systemic IL-2 infusion. This approach represents a novel application of MoAb technology, in that MoAbs are used not to diagnose or treat disease directly but rather to identify lymph node cells with therapeutic potential.

Adult↗
PubMed1999

Cellular immunotherapy of advanced human immunodeficiency virus type 1 infection using autologous lymph node lymphocytes: effects on chemokine production.

A pilot study was undertaken in patients with human immunodeficiency virus type 1 (HIV-1) infection to examine the effects of infusing autologous lymph node lymphocytes that had been cultured ex vivo in conditions designed to maximize the specific secretion of HIV-1-suppressive factors, including beta chemokines. Ten patients with CD4 cell counts between 119 and 436/microliter on antiretroviral drugs received a single infusion of CD4 and CD8 lymph node lymphocytes. There were no serious acute or chronic adverse clinical effects. Increases in serum levels of macrophage inflammatory protein 1beta (MIP-1beta) and increases in the production of MIP-1beta by peripheral blood lymphocytes in response to HIV-1 env were observed. Increases in CD4 and CD8 cell counts and skin test reactivity to recall antigens and decreases in HIV-1 virus load were also observed. This cellular immunotherapy can modulate beta chemokine production in patients with advanced HIV-1 infection and may contribute immunorestorative and antiviral activities.

Blood Transfusion, Autologous↗
PubMed1999

Low-dose monoclonal antibody CC49 administered sequentially with granulocyte-macrophage colony-stimulating factor in patients with metastatic colorectal cancer.

The clinical and immunologic effects of murine monoclonal antibody (mAb) CC49 administered at a low dose sequentially with granulocyte-macrophage colony-stimulating factor (GM-CSF) were examined. Fourteen patients with metastatic colorectal cancer received 1 mg of unconjugated CC49 on day 1; on day 15 they began 125 micrograms/m2 GM-CSF by subcutaneous injection daily for 14 days, followed by 7 days of rest. Another 14 days of GM-CSF were then administered, followed by 7 days of rest. This 56-day cycle was repeated in patients whose cancer did not progress. Therapy was well tolerated; adverse allergic reactions were not observed. Objective tumor responses were not observed. Increases in antiidiotypic (T2) and anti-antiidiotypic (T3) cellular responses were observed, as were increases in human antimouse antibody levels. In contrast, the expression of Fc receptors on CD14+ peripheral blood monocytes decreased. This pilot study demonstrates idiotypic cellular immunologic effects of antitumor murine mAb, even at the doses used for imaging, and supports the sequential administration of GM-CSF as an adjuvant to mAb-based immunogens.

Adult↗
PubMed1998

HIV type 1-reactive chemokine-producing CD8+ and CD4+ cells expanded from infected lymph nodes.

The chemokines RANTES, MIP-1alpha, and MIP-1beta have been identified as HIV-1-suppressive factors produced by CD8+ T cells. We examined the possibility that HIV-1-specific, chemokine-releasing T cells could be expanded from the lymph nodes of patients with advanced infection. Lymphocytes, separated from lymph nodes of patients with peripheral blood CD4 counts less than 500/microl obtained at diagnostic biopsies, were activated with anti-CD3 monoclonal antibody, and cultured in vitro for up to 12 days with IL-2. The phenotype, proliferative response, chemokine production, and anti-HIV-1 activity of the expanded cells was examined. Cells expanded 2.4- to 49-fold from patients with as few as 15 CD4+ cells/microl in their peripheral blood. Expanded cells were a mixture of CD8+CD45RO+ and CD4+CD45RO+ T cells. The CD8+ cells were also CD30+CDw60+CD11b-. When challenged with autologous B cell targets expressing HIV-1 Env protein, unseparated expanded cells, and purified CD8+ and CD4+ T cell subsets, proliferated and secreted MIP-1alpha and RANTES. Expanded cells were negative for HIV-1 by PCR and by culture. Culture supernatants inhibited the replication of HIV-1 in CD4+ cells in vitro. These studies indicate that HIV-1 can stimulate chemokine release by CD8+ and CD4+ cells expanded from infected lymph nodes, even from individuals with advanced infection. The numbers of chemokine-releasing T cells produced in these short-term cultures may be sufficient to be applied therapeutically as an autologous cellular therapy for HIV-1.

CD4 Lymphocyte Count↗
PubMed1998

Iodination of human thyroglobulin (Tg) alters its immunoreactivity. I. Iodination alters multiple epitopes of human Tg.

Human Tg, the site of synthesis of thyroid hormones, thyroxine (T4) and triiodothyronine (T3), is one of the major autoantigens in autoimmune thyroiditis. The degree of iodination of Tg may have a major impact on its immunological properties by changing its antigenicity with respect to antibody binding. We have previously prepared a panel of MoAbs that bind to different epitopes of the Tg molecule. In the present study, we show that iodination alters the conformation of Tg molecule in such a way that it is recognized differently by different MoAbs. Monoclonal antibody 137C1 recognizes Tg regardless of its iodine content. Monoclonal antibody 42C3 recognizes Tg only if the Tg is iodinated either in vitro or in vivo. Monoclonal antibody 133B1 recognizes both in vivo iodinated Tg and non-iodinated Tg, but this MoAb did not recognize Tg following in vitro iodination. Monoclonal antibody 41A5 recognizes intact Tg and tryptic peptides of normal (in vivo) iodinated and non-iodinated Tg, but did not bind the tryptic peptides of artificially (in vitro) iodinated Tg. From the results of these experiments, we conclude that iodination of Tg by either in vivo or in vitro methods changes its conformation in such a way that some natural epitopes are 'lost' and some 'new' epitopes are generated. The generation of new epitopes may be important in the generation of autoimmune responses leading to autoimmune disease.

Antibodies, Monoclonal↗
PubMed1994

Immunoreactivity of multiple molecular forms of human thyroglobulin.

Human thyroglobulin (Tg) was purified from thyroids of normal individuals and of patients with Graves' disease using gel filtration (Sephacryl S-400) and ion-exchange (DEAE) column chromatography. We isolated five protein peaks of Tg from the DEAE column, using a step gradient, characterized them for protein and iodine content, and assessed their immunological properties by reactivity to polyclonal and monoclonal antibodies (mAbs). Normal and Graves' Tgs differed in the relative protein content of these five protein peaks from the DEAE column. In the case of normal Tg, the majority of Tg was eluted in peak 2 but in the Graves' Tg, most of the protein was eluted in peak 1 of this column. The immunoreactivity of these five protein peaks of Tg was studied using 11 mouse mAbs prepared against human Tg, sera from patients with autoimmune thyroiditis and polyclonal antibody from a rabbit immunized with human Tg. All of five protein peaks of Tg reacted equally with rabbit antibody. The sera of five thyroiditis patients showed greater binding to peak 1 of Graves' Tg than peak 1 of normal Tg. Similarly, most mAbs showed greater binding to peak 1 of Graves' Tg than the peak 1 of normal Tg. Of particular interest was one mAb (42C3) which reacted only with Tgs containing iodine. The immunoreactivity of this mAb paralleled the iodine content of Tg. This mAb might be useful for evaluating the role of iodine in the antigenicity of human Tg.

Antibodies, Monoclonal↗
PubMed1994

Tryptic peptides of human thyroglobulin: I. Immunoreactivity with murine monoclonal antibodies.

Human thyroglobulin (Tg) was treated with trypsin at different concentrations of trypsin/Tg for various incubation times at 37 degrees C using non-reducing conditions. A ratio of trypsin to Tg of 1:100 (w/w) was optimal to release small peptides that were reactive to murine MoAbs to human Tg. Most peptides were released after only 1 h incubation with trypsin, but these peptides were further degraded at longer incubation times. However, a few small peptides, the largest of which with an apparent molecular weight (MWap) of 40 kD, resisted tryptic digestion up to at least 12 h of incubation. These resistant peptides were further degraded by trypsin at 18-24 h of incubation. Tryptic peptides of Tg, released at 1 h and 4 h of incubation, were analysed for their immunoreactivity to 16 well characterized anti-Tg MoAbs by Western immunoblot. Patterns of peptide recognition of these MoAbs were generally unique. Eight MoAbs reacted with peptides of MWap of 10-25 kD and above. Four other MoAbs reacted with peptides of MWap of 25-43 kD and above, and the remaining four reacted with peptides of MWap > 43 kD. Nine of these MoAbs failed to recognize peptides after reduction, suggesting that the MoAbs bind conformation-dependent epitopes. The above information will promote the development of models relating the structure of Tg to the autoimmune process, and may provide an understanding of those regions of Tg responsible for the induction of autoimmune thyroiditis.

Animals↗
PubMed1990

Autoantigenic determinants on human thyroglobulin. I. Determinant specificities of murine monoclonal antibodies.

To map the antigenic determinants, a panel of 20 mouse monoclonal antibodies (mAbs) to native human thyroglobulin (Tg) was generated. Four criteria were established for distinguishing the determinants recognized by the various mAbs: (i) reactivity to Tgs from eight different species; (ii) reactivity to oxidized and reduced human Tg; (iii) the ability of thyroxine to inhibit binding of mAbs; and (iv) the pattern of antigenic determinant reactivity as determined in reciprocal competitive inhibition binding assays. Of 20 mAbs examined, 12 bound only to human Tg, 3 bound to all eight species tested, and 5 bound to human Tg and to Tg from at least one of the other seven species. Eight mAbs bound oxidized/reduced and native human Tg equally well, 2 bound to the oxidized/reduced protein better than to the native, 7 showed virtually no reactivity to oxidized/reduced human Tg, and 3 others reacted to the oxidized/reduced protein significantly less than they bound to the native. The binding of 5 mAbs to native human Tg was inhibited by thyroxine. The pattern of shared determinant specificities revealed that at least 12 determinant clusters were defined by the panel of mAbs. Among the 12 determinant clusters were 3 designated as immunodominant; 8 of 20 mAbs defined these immunodominant clusters. The four criteria taken together indicate that at least 19 different epitopes on human Tg could be distinguished by this panel of mAbs. These mAbs are useful for the study of determinant specificities of Tg autoantibodies in humans.

Animals↗
PubMed1990

Autoantigenic determinants on human thyroglobulin. II. Determinants recognized by autoantibodies from patients with chronic autoimmune thyroiditis compared to autoantibodies from healthy subjects.

Using a panel of 20 well-characterized mouse monoclonal antibodies (mAbs) to native human thyroglobulin (Tg), the fine specificities of autoantibody responses in human autoimmune thyroiditis patients were compared to naturally occurring autoantibodies from healthy individuals. The antigenic determinants recognized by the human autoantibodies were assessed using competitive binding assays in which murine mAbs were inhibited by human autoantibodies. All determinants of human Tg recognized by the mouse were also responded to by the human subjects. Autoantibodies from adult and juvenile patients with chronic lymphocytic thyroiditis recognized principally 10 of 19 determinants defined by the panel of murine mAbs. The mAbs which define these 10 determinants do not react with Tg from seven other mammalian species; therefore, autoantibody responses in individuals with thyroiditis are directed primarily to species specific determinants of human Tg. These same determinants on human Tg were the principal ones recognized by the mouse following immunization. Particular patterns of fine specificities were not inherited from parents by probands or their siblings, even if identical twins. Naturally occurring Tg autoantibodies from healthy subjects recognized mainly thyroxine-containing cross-reactive determinants.

Adolescent↗
PubMed1990

Mapping the autoepitopes of thyroglobulin.

Chronic thyroiditis is currently the best available model of an organ-restricted autoimmune disease, because the principle antigen Tg is a well-characterized protein and the disease can be reproduced by experimental immunization. The pattern of autoantigenic determinants of Tg that is recognized by sera from subjects without detectable thyroid disease is clearly different from that seen with thyroiditis patients. Both sets of sera react with the evolutionary conserved portions, the hormonogenic regions containing the T3 and T4 moieties. Sera of thyroiditis patients, however, also react with the evolutionary variable, species-specific portions of the Tg molecule. Mice immunized with human Tg respond to the same, immunodominant sites. Mice injected with mouse Tg preferentially recognize the analogous, mouse-specific sites of Tg. Mice are not restricted, however, in their use of V-(D)-J genes for Ig production, even when the same antigenic determinant is involved.

Animals↗
PubMed1990

Human autoimmune thyroid disease: risk factors.

Genetics sets the groundwork for the predisposition to autoimmune thyroid disease, and in certain individuals, such as the juveniles presented here, very little impetus is needed to push normal immune reactions to autoimmune disease. However, in individuals who inherit only a few of these traits, the accumulation of many developmental and environmental insults may promote the development of disease.

Animals↗