| 1. |
- Hojjat-Farsangi, Mohammad, et al.
(författare)
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Immunophenotypic characterization of the leukemic B-cells from Iranian patients with chronic lymphocytic leukemia : association between CD38 expression and disease progression
- 2008
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Ingår i: Iranian Journal of Immunology. - Stockholm : Karolinska Institutet, Dept of Oncology-Pathology. - 1735-1383.
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Tidskriftsartikel (refereegranskat)abstract
- Background: Patients with B-cell chronic lymphocytic leukemia (B-CLL) have heterogeneous clinical courses, thus several biological parameters need to be added to the current clinical staging systems to predict disease outcome. Recent immunophenotypic studies performed mainly in Western populations have demonstrated the prognostic value of CD38 and ZAP-70 expression in B-CLL. Objectives: To investigate the expression pattern of a variety of membrane antigens on leukemic cells from Iranian patients with CLL and to find out if there are any differences in the expression of these markers between indolent and progressive groups. Methods: In the present study, peripheral blood samples from 87 Iranian patients with B-CLL were analysed by flow cytometry. Results: In all cases, the neoplastic cells displayed B-CLL phenotype (CD5+/CD19+/sIg+). The vast majority of the cases expressed CD23, but failed to stain for CD3 or CD14. The leukemic cells of most patients expressed CD27 (84/87, 95.4%) and CD45RO (74/87, 83.9%) molecules, suggesting a memory B-cell phenotype. Comparison between the indolent (n=42) and progressive (n=37) patients revealed significantly higher frequency and intensity of CD38 expression in progressive group (40.5%) compared to indolent (11.9%) patients (p<0.05). None of the other membrane antigens were differentially expressed in these two groups of patients. Conclusion: Our results obtained in an Asian ethnic population confirm and extend previous findings obtained from Western populations regarding the association of CD38 expression and disease progression in B-CLL.
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| 2. |
- Hojjat-Farsangi, Mohammad, et al.
(författare)
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RETRACTED: Inhibition of the receptor tyrosine kinase ROR1 by anti-ROR1 monoclonal antibodies and siRNA induced apoptosis of melanoma cells
- 2013
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Ingår i: PLOS ONE. - Stockholm : Karolinska Institutet, Dept of Oncology-Pathology. - 1932-6203.
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Tidskriftsartikel (refereegranskat)abstract
- RETRACTED ARTICLE. Retraction: PLoS One. 2022 May 5;17(5):e0268357. The receptor tyrosine kinase (RTK) ROR1 is overexpressed and of importance for the survival of various malignancies, including lung adenocarcinoma, breast cancer and chronic lymphocytic leukemia (CLL). There is limited information however on ROR1 in melanoma. In the present study we analysed in seven melanoma cell lines ROR1 expression and phosphorylation as well as the effects of anti-ROR1 monoclonal antibodies (mAbs) and ROR1 suppressing siRNA on cell survival. ROR1 was overexpressed at the protein level to a varying degree and phosphorylated at tyrosine and serine residues. Three of our four self-produced anti-ROR1 mAbs (clones 3H9, 5F1 and 1A8) induced a significant direct apoptosis of the ESTDAB049, ESTDAB112, DFW and A375 cell lines as well as cell death in complement dependent cytotoxicity (CDC) and antibody dependent cellular cytotoxicity (ADCC). The ESTDAB081 and 094 cell lines respectively were resistant to direct apoptosis of the four anti-ROR1 mAbs alone but not in CDC or ADCC. ROR1 siRNA transfection induced downregulation of ROR1 expression both at mRNA and protein levels proceeded by apoptosis of the melanoma cells (ESTDAB049, ESTDAB112, DFW and A375) including ESTDAB081, which was resistant to the direct apoptotic effect of the mAbs. The results indicate that ROR1 may play a role in the survival of melanoma cells. The surface expression of ROR1 on melanoma cells may support the notion that ROR1 might be a suitable target for mAb therapy.
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| 3. |
- Jeddi-Tehrani, Mahmood, et al.
(författare)
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Construction and characterization of a new chimeric antibody against HER2
- 2013
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Ingår i: Immunotherapy. - Stockholm : Karolinska Institutet, Dept of Oncology-Pathology. - 1750-743X .- 1750-7448.
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Tidskriftsartikel (refereegranskat)abstract
- Aim: Immunotherapy with anti-HER2 antibodies has shown promising results in patients with HER2-positive breast cancer. We have recently reported characterization of a mouse monoclonal antibody (mAb) against HER2, which binds to an epitope different from that recognized by trastuzumab and specifically inhibits proliferation of tumor cells overexpressing HER2. In the present study we report chimerization of this antibody. Materials & methods: The immunoglobulin variable region heavy and light chain genes of 1T0 hybridoma cells were amplified and ligated to human -1 and constant region genes using splice overlap extension PCR. The chimeric antibody was subsequently expressed and characterized by ELISA, western blot and flow cytometry. Results: The purified chimeric antibody specifically binds to recombinant HER2 and HER2-overexpressing tumor cells and inhibits proliferation of these cells. The binding affinity of the chimeric mAb was comparable with the parental mouse mAb. Conclusion: This chimeric anti-HER2 mAb is a potentially valuable tool for targeted immunotherapy.
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| 4. |
- Rabbani, Hodjatallah
(författare)
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Evolutionary aspects of the immunoglobulin heavy chain constant locus
- 1997
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The human Ig heavy chain constant locus (IGHC) is composed of nine functional and two pseudo genes. Extensive polymorphism consisting of deletions, duplications and point mutations have been observed in this locus. The mechanism underlying these deletions and duplications have been postulated to be either non-equal homologous recombination during the meiosis or looping out excision. As a part of this study, 15 patients with selective IgG1 deficiency were screened for IGHC deletions. The frequency of deletions among immunodeficient patients was 19%. In another study the influence of gene duplications on serum level of antibody in 63 healthy Caucasian individuals with heterozygous duplications (encompassing G2 and G4) was determined. No consistent positive influence of duplications on serum levels of either IgG2 or IgG4 was observed. Study of the influence of gene deletions on serum level of antibody in individuals with heterozygous gene deletions encompassing Cyl gene showed significant decrease on serum levels of IgG1 but a significant increase of IgG3 levels. Individuals with heterozygous deletions of the Cy2 and Cy4 also showed significant decreases in serum levels of the affected subclass. In a study on 500 healthy individuals from three major human races (Negroid, Mongoloid and Caucasoid), the highest haplotype frequency of duplications was found in the Mongoloid population (22%), followed by the Caucasian (10%) and Negroid population (5%). The corresponding frequencies of deletions were 2, 1.5, and 3.5%, respectively. New types of multiple and single duplications (IGHGl-IGHG4, IGHEPI-IGHG2, IGHGP) were found in this study. The most common duplication, found in all populations studied, encompasses the IGHAI-IGHE genes. The only deletion common to all racial groups was an isolated deletion of the IGHG4 gene. To date, fifteen distinct IGHC deletion haplotypes and nine IGHC duplications have been described. In two other studies, the bovine genes for Ca and Cy3 were cloned and sequenced. The results revealed that there are three gamma genes, one Ca, one Cu and one Ce gene in the bovine immunoglobulin heavy chain constant region gene locus. A small duplication of 84 bp in the bovine IGHG3 gene, possibly resulting from an unequal crossing-over was found, confirming the same mechanism as in human. Altogether, these studies show that the Ig heavy chain constant locus is continuously being affected by new deletions and duplications, leading to immunoglobulin diversity. The evolutionary process of the IGHC locus appears to be progressive.
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| 5. |
- Shabani, Mahdi, et al.
(författare)
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Comparative expression profile of orphan receptor tyrosine kinase ROR1 in Iranian patients with lymphoid and myeloid leukemias
- 2011
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Ingår i: Avicenna Journal of Medical Biotechnology. - Stockholm : Karolinska Institutet, Dept of Oncology-Pathology. - 2008-2835.
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Tidskriftsartikel (refereegranskat)abstract
- It has recently been shown that ROR1, a member of the receptor tyrosine kinase family, is overexpressed in leukemic B cells of Chronic Lymphocytic Leukemia (CLL) and a subset of Acute Lymphoblastic Leukemia (ALL). In this comparative study the expression profile of ROR1 mRNA was investigated in Iranian patients with CLL and Acute Myelogenous Leukemia (AML) and the results were compared with those previously reported in our Iranian ALL patients. RT-PCR was performed on bone marrow and/or peripheral blood samples of 84 CLL and 12 AML patients. CLL samples were classified into immunoglobulin heavy chain variable region (IGHV) gene mutated (n = 55) and unmutated (n = 29) and also indolent (n = 42) and progressive (n = 39) subtypes. ROR1 expression was identified in 94% of our CLL patients, but none of the AML patients expressed ROR1. No significant differences were observed between different CLL subtypes for ROR1 expression. Taken together the present data and our previous results on ROR1 expression in ALL, our findings propose ROR1 as a tumor-associated antigen overexpressed in a large proportion of lymphoid (CLL and ALL), but not myeloid (AML) leukemias. Expression of ROR1 seems to be associated to lineage and differentiation stages of leukemic cells with a potential implication for immunotherapy.
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| 6. |
- Shabani, Mahdi, et al.
(författare)
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Ligation of human Fc receptor like-2 (FCRL2) by monoclonal antibodies downregulates B cell receptor mediated signaling
- 2014
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Ingår i: Immunology. - Stockholm : Karolinska Institutet, Dept of Oncology-Pathology. - 0019-2805 .- 1365-2567.
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Tidskriftsartikel (refereegranskat)abstract
- B cell antigen receptor (BCR) signaling and its regulation through negative and positive regulators are critical for balancing B cell response and function. Human Fc receptor like-2 (FCRL2), a member of the newly identified FCRL family, could influence B cell signaling due to possession of both immunoreceptor tyrosine-based activation and inhibitory motifs (ITAM and ITIM). Since the natural ligand of FCRL2 has not been identified yet, we generated FCRL2-specific monoclonal antibodies (mAbs) and employed them to investigate the influence of FCRL2 stimulation on BCR signaling in a FCRL2-expressing B cell line. Two anti-FCRL2 mAb-producing hybridoma clones (5A7-E7 and 3D8-G8) were selected. None of the mAbs displayed any cross-reactivity with the other members of the FCRL family including recombinant FCRL1, 3, 4 and 5, as tested by FACS and ELISA techniques. Engagement of the FCRL2 by these mAbs resulted in significant inhibition of BCR signaling mediators such as calcium mobilization and phosphorylation of the MAP kinases Erk, p38 and Jnk MAP. These findings indicate that the FCRL2 ITIM motifs are functional and the anti-FCRL2 mAbs may mimic the natural ligand of FCRL2 by induction of inhibitory signals in B cells.
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| 7. |
- Ullenhag, Gustav, et al.
(författare)
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Immunization of colorectal carcinoma patients with a recombinant canarypox virus expressing the tumor antigen Ep-CAM/KSA (ALVAC-KSA) and granulocyte macrophage colony- stimulating factor induced a tumor-specific cellular immune response
- 2003
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 9:7, s. 2447-2456
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Colorectal carcinoma cells express the tumor-associated antigen epithelial cellular adhesion molecule (Ep-CAM)/KSA. Passive immunotherapy with monoclonal antibodies using this antigen has shown promising results. Ep-CAM might also be a target for active specific immunotherapy. Expression of the tumor antigen in a viral vector may facilitate appropriate antigen presentation. The feasibility of an Ep-CAM/KSA-specific therapeutic vaccination was investigated in cancer patients.EXPERIMENTAL DESIGN: The full-length Ep-CAM gene was inserted into the avipox virus ALVAC (ALVAC-KSA). Twelve radically operated colorectal carcinoma patients without evidence of remaining macroscopic disease (stages I, II, and III) entered the study. The first 6 patients were immunized with three injections of ALVAC-KSA (10(7.09) CCID(50) per immunization) alone in weeks 0, 3, and 6. The subsequent 6 patients received the same schedule of ALVAC-KSA together with the adjuvant cytokine granulocyte macrophage colony-stimulating factor (GM-CSF; 75 micro g/day for 4 consecutive days).RESULTS: The adverse reactions to the vaccinations were mild except for local skin reactions. In the ALVAC-KSA group a weak T-cell response was induced in 2 of 6 patients. In the ALVAC-KSA/GM-CSF group a marked IFN-gamma response (enzyme-linked immunospot) was induced in 5 of 6 patients. The T-cell response appeared late, 1 month after the last immunization, with a peak at 4-5 months after immunization. No IgG antibodies against Ep-CAM were detected. Before vaccination the majority of patients had a type 1 T-cell response (IFN-gamma) against the vector, which was noted in healthy donors as well. All of the patients developed high titers of IgG antibodies against the vector, and the T-cell response was vigorously boosted.CONCLUSIONS: ALVAC-KSA, in combination with low dose local administration of GM-CSF may induce a strong, IFN-gamma T-cell response (type 1). ALVAC-KSA seems to be an interesting candidate as a cancer vaccine for future clinical development.
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