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PubMed2002

Prevention of chronic rejection in murine cardiac allografts: a comparison of chimerism- and nonchimerism-inducing costimulation blockade-based tolerance induction regimens.

We have previously described a nonirradiation-based regimen combining costimulation blockade, busulfan, and donor bone marrow cells that promotes stable, high level chimerism, deletion of donor-reactive T cells, and indefinite survival of skin allografts in mice. The purpose of the current study is to determine the efficacy of this tolerance regimen in preventing acute and chronic rejection in a vascularized heart graft model and to compare this regimen with other putative tolerance protocols. Mice receiving costimulation blockade (CTLA4-Ig and anti-CD40 ligand) alone or in combination with donor cells enjoyed markedly prolonged heart graft survival and initially preserved histological structure. However, tolerance was not achieved, as evidenced by the eventual onset of chronic rejection characterized by obliterative vasculopathy and the rejection of secondary skin grafts. In contrast, following treatment with costimulation blockade, busulfan, and bone marrow, heart grafts survived indefinitely without detectable signs of chronic rejection or structural damage, even 100 days after placement of a secondary donor skin graft. We detected multilineage chimerism in peripheral blood, spleen, lymph nodes, and thymus, and peripheral deletion of donor-reactive cells was complete by day 90. These findings indicate that only the CD40/CD28 blockade chimerism induction regimen prevents both acute and chronic rejection of vascularized organ transplants. Further testing of these strategies in a preclinical large animal model is warranted.

Acute Disease↗
PubMed2004

A caspase-6 and anti-human epidermal growth factor receptor-2 (HER2) antibody chimeric molecule suppresses the growth of HER2-overexpressing tumors.

Clinical studies have suggested that human epidermal growth factor receptor-2 (HER2) provide a useful target for antitumor therapy. We previously described the generation of a chimeric HER2-targeted immunocasp-3 protein. In this study, we extend the repertoire of chimeric proapoptotic proteins with immunocasp-6, a construct that comprises a HER2-specific single-chain Ab, a single-chain Pseudomonas exotoxin A, and an active caspase-6, which can directly cleave lamin A leading to nucleus damage and inducing programmed cell death. We demonstrate that the secreted immunocasp-6 molecule selectively recognizes and induces apoptosis in HER2-overexpressing tumor cells in vitro, but not in cells with undetectable HER2. The immunocasp-6 gene was next transferred into BALB/c athymic mice bearing human breast SK-BR-3 tumors by i.m. injection of liposome-encapsulated vectors, by intratumor injection of adenoviral vectors, or by i.v. injection of PBMC modified by retroviral infection. Regardless of the method used, expression of immunocasp-6 suppressed tumor growth and prolonged animal survival significantly. Our data show that the chimeric immunocasp-6 molecule can recognize HER2-positive tumor cells, promptly attack their nucleus, and induce their apoptotic death, suggesting the potential of this strategy for the treatment of human cancers that overexpress HER2.

ADP Ribose Transferases↗
PubMed2006

Partial versus full allogeneic hemopoietic chimerization is a preferential means to inhibit type 1 diabetes as the latter induces generalized immunosuppression.

In both humans and NOD mice, particular combinations of MHC genes provide the primary risk factor for development of the autoreactive T cell responses causing type 1 diabetes (T1D). Conversely, other MHC variants can confer dominant T1D resistance, and previous studies in NOD mice have shown their expression on hemopoietically derived APC is sufficient to induce disease protection. Although allogeneic hemopoietic chimerization can clearly provide a means for blocking T1D development, its clinical use for this purpose has been obviated by a requirement to precondition the host with what would be a lethal irradiation dose if bone marrow engraftment is not successful. There have been reports in which T1D-protective allogeneic hemopoietic chimerization was established in NOD mice that were preconditioned by protocols not including a lethal dose of irradiation. In most of these studies, virtually all the hemopoietic cells in the NOD recipients eventually converted to donor type. We now report that a concern about such full allogeneic chimeras is that they are severely immunocompromised potentially because their T cells are positively selected in the thymus by MHC molecules differing from those expressed by the APC available in the periphery to activate T cell effector functions. However, this undesirable side effect of generalized immunosuppression is obviated by a new protocol that establishes without a lethal preconditioning component, a stable state of mixed allogeneic hemopoietic chimerism sufficient to inhibit T1D development and also induce donor-specific tolerance in NOD recipients.

Animals↗
PubMed1999

Requirements for signal delivery through CD44: analysis using CD44-Fas chimeric proteins.

CD44 is a transmembrane glycoprotein involved in various cell adhesion events, including lymphocyte migration, early hemopoiesis, and tumor metastasis. To examine the requirements of CD44 for signal delivery through the extracellular domain, we constructed a chimeric CD44 protein fused to the intracellular domain of Fas on its C-terminus. In cells expressing the CD44-Fas fusion protein, apoptosis could be induced by treatment with certain anti-CD44 mAbs alone, especially those recognizing the epitope group d, which has been previously shown to play a role in ligand binding, indicating that ligation of a specific region of the CD44 extracellular domain results in signal delivery. Of note was that appropriate ligation of the epitope h also resulted in the generation of apoptotic signal, although this region was not thought to be involved in ligand binding. In contrast, the so-called blocking anti-CD44 mAbs (epitope group f) that can abrogate the binding of hyaluronate (HA) failed to induce apoptosis even after further cross-linking with the secondary Ab, indicating that a mere mAb-induced oligomerization of the chimeric proteins is insufficient for signal generation. However, these blocking mAbs were instead capable of inhibiting apoptosis induced by nonblocking mAb (epitope group h). Furthermore, a chimeric protein bearing a mutation in the HA binding domain and hence lacking the ability to recognize HA was incapable of mediating the mAb-induced apoptosis, suggesting that the functional integrity of the HA binding domain is crucial to the signal generation in CD44.

Animals↗
PubMed2000

Hepatitis C epitopes from phage-displayed cDNA libraries and improved diagnosis with a chimeric antigen.

A novel method for cloning DNase I fragments into bacteriophage display vector fUSE2 was used to create libraries expressing hepatitis C virus (HCV) protein fragments on the phage surface. Selection by panning with a mixture of sera from five HCV-seropositive individuals enabled identification of antigenic determinants in NS3 (amino acids 1,383-1,415), NS4 (amino acids 1, 930-1,938), and NS5 (amino acids 2,088-2,104). The NS3 result is the most accurate location to date of a major conformational determinant that cannot be mimicked by short peptides. Any expressed sequence from the phage library can be excised with Bgl II and cloned directly into the Bgl II site of an appropriate plasmid for bacterial expression. This enables production of chimeric proteins containing multiple antigenic determinants, illustrated by co-expression of the NS4P (amino acids 1,930-1,938) epitope with an NS4N fragment (amino acids 1,644-1,812) containing at least three linear HCV epitopes. When used to screen 35 individual HCV-positive sera by enzyme-linked immunosorbent assay (ELISA), the chimeric antigen detected eight more positives than NS4N alone and gave increased immunoreactivity with others. This approach of identifying antigenic regions by phage display and then co-expressing them as chimeric proteins may be generally applicable to the production of improved diagnostic antigens and recombinant vaccines.

Amino Acid Sequence↗
PubMed2000

Myeloid mixed chimerism is associated with relapse in bcr-abl positive patients after unmanipulated allogeneic bone marrow transplantation for chronic myelogenous leukemia.

BACKGROUND AND OBJECTIVE: Although bcr-abl polymerase chain reaction (PCR) positivity after bone marrow transplantation (BMT) for chronic myelogenous leukemia (CML) is significantly related to relapse, the predictive value of the assay is not very high and therefore most investigators consider that qualitative RT-PCR data alone are too imprecise to enable clinical decisions to be taken in individual cases. To define the clinical outcome of bcr-abl positive patients after unmanipulated BMT better, we sought the origin of hematopoiesis and traced its evolution over time. DESIGN AND METHODS: Forty-nine patients received allogeneic BMT for CML (39 in chronic phase and 10 in accelerated phase/blast crisis). Median follow-up was 61 months (range 4-92). mRNA and DNA were used to assess bcr-abl and chimerism status respectively. Quantitative VNTR-PCR on total cells and lymphoid or myeloid population allowed us to assign and measure the origin of hematopoiesis. RESULTS: Both bcr-abl positivity and the presence of mixed chimerism (MC) were significantly associated with relapse (p = 0.0009 and p < 0.0001 respectively). Relapse was observed in one of 39 patients with complete donor chimerism and in 6 of 9 patients with MC. These six cases showed increasing levels of host hemopoiesis and bcr-abl positivity in the CD15-positive population prior to relapse. The other three cases had decreasing or stable low-level MC which was restricted to the T-cells as well as bcr-abl negativity. INTERPRETATION AND CONCLUSIONS: Whereas the simple detection of bcr-abl fails to identify patients who will relapse with certainty, the assessment of MC by VNTR-PCR does identify patients headed to relapse. Confirmation of myeloid involvement and increasing levels over time further elucidates the clinical outcome of bcr-abl positive patients after BMT.

Adolescent↗
PubMed2000

Recombinant adenovirus vaccine encoding a chimeric T-cell antigen receptor induces protective immunity against a T-cell lymphoma.

Vaccination using recombinant tumor-derived T-cell antigen receptor (TCR) protein induces a protective, idiotype-specific immune response against a murine T-cell tumor. However, the technically demanding task of producing patient-specific, recombinant TCR protein restricts the translation of TCR vaccines for clinical use. We report here the development of an effective recombinant TCR adenovirus vaccine. Individual adenoviruses were constructed to encode a chimeric TCR derived from either tumor Valpha or Vbeta regions fused to xenogeneic human constant regions. Coinjection of the chimeric alpha- and the beta-TCR adenoviruses protected mice against tumors. The level of protection was comparable to that achieved by an optimized regimen of recombinant TCR protein vaccines. Tumor immunity induced by TCR adenoviruses required the xenogeneic constant regions and was mediated by CD8+ T cells. Independent vaccines consisting of adenovirus expressing either chimeric alpha- or beta-TCR chain also stimulated a protective immune response. Immunization with TCR adenovirus may offer a new efficacious, protein-free vaccination approach for the treatment of T-cell malignancies.

Animals↗
PubMed2000

[Hydrolysis of chimeric proteins by enteropeptidase at the specific linker (Asp)4Lys depending on refolding conditions].

Refolding from inclusion bodies of chimeric proteins containing the enteropeptidase-specific linker (Asp)4Lys was carried out. It was shown that, depending on the refolding conditions, chimeric proteins function as substrates or inhibitors of the enteropeptidase. The efficiency of the enteropeptidase hydrolysis of chimeric proteins containing the (Asp)4Lys linker may depend not only on the amino acid sequence of the protein binding site for the enzyme but also on the site conformation.

Aspartic Acid↗
PubMed2000

Cross-chimeric analysis of selectivity of secretin and VPAC(1) receptor activation.

Agonist action at receptors is highly specific, affected by the structure of both ligand and receptor. Chimeric constructs of structurally related receptors and/or ligands that have biological differences provide an opportunity to correlate a specific structural domain with function. In this work, we have used a cross-chimeric approach to explore the structural basis for rat secretin and vasoactive intestinal polypeptide action at their closely related secretin and VPAC(1) receptors, belonging to class II of the G protein-coupled receptor superfamily. Multiple domains of both ligands and receptors contributed toward their selectivity, with differing combinations of such domains able to support high-potency interactions. The amino-terminal 15 residues of secretin were most critical for potent stimulation of secretin receptors, whereas either the amino- or carboxyl-terminal halves of vasoactive intestinal polypeptide, when complemented by Lys(15), provided potent stimulation of the VPAC(1) receptor. The amino terminus of the VPAC(1) receptor was most critical for potent response to vasoactive intestinal polypeptide, whereas the amino terminus of the secretin receptor was important, but not adequate, requiring the complementation of an extracellular loop domain for potent response to secretin. Differences in the distribution of these determinants within these receptors provided an opportunity to produce a more "universal" receptor that contained the first extracellular loop of the secretin receptor and the remainder of the VPAC(1) receptor. This cross-chimeric approach should be applied to other members of this receptor family to test the emerging themes and to expand these insights as broadly as possible.

Amino Acid Sequence↗
PubMed2001

Transplantation tolerance and mixed chimerism: at the frontier of clinical application.

Although the persistence of donor-type hematopoietic cells in low numbers (microchimerism) is well established in some transplant recipients, its relevance for graft acceptance is still a matter of debate. On the other hand, clonal deletion of donor-specific alloreactive cells associated with mixed chimerism (macrochimerism) has reliably produced long-term graft tolerance in pre-clinical models. So far, the cytoablative conditioning regimens required to achieve mixed chimerism have hampered the clinical development of such protocols. Here, we discuss recent observations suggesting that the deliberate induction of hematopoietic cell chimerism might become a feasible strategy to achieve transplantation tolerance in clinics.

Animals↗
PubMed2001

[Complex translocation (8;15;21) (q22;p12;q22) in a child with AML-M2 showing de novo appearance of the short form of AML1-MTG8 chimeric mRNA during the course].

A 4-year-old boy admitted with exophthalmos was diagnosed as having acute myeloblastic leukemia with maturation (AML-M2). Chromosomal analysis (G-banding) showed t(8;15;21). Fluorescence in situ hybridization (FISH), reverse transcriptase-polymerase chain reaction (RT-PCR), spectral karyotyping (SKY), and nucleolar organizer region (NOR) staining suggested that this complex translocation might have resulted from stepwise translocation, namely an initial translocation between chromosomes 8 and 21, followed by a second translocation between der(21) and chromosome 15, rather than the other possibility of clockwise translocation. During chemotherapy, RT-PCR demonstrated the short form of AML1-MTG8 mRNA, in addition to chimeric mRNA of the usual length. Sequence analysis revealed that this shorter chimeric mRNA had resulted from deletion of a 250-bp sequence at the 5' end of MTG8. A literature search failed to reveal any similar cases of t(8;21) AML-M2 associated with this deletion of chimeric mRNA.

Base Sequence↗
PubMed1999

Effects of the configuration of a multi-epitope chimeric malaria DNA vaccine on its antigenicity to mice.

OBJECTIVE: Four B and Th cell epitopes were selected from conservative domain of Plasmodium falciparum antigens to construct two groups of chimeric malaria DNA vaccines with different configurations and their antigenicities were studied. METHODS: The partially synthesized oligonucleotide was annealed, PCR amplified and cloned into a mammalian cell expression vector. By using a pair of isocaudamers on the vector, different single copies of B epitopes were multiplied and were tenderly stringed into two groups of chimeric DNA vaccine with different configurations. BALB/c mice were immunized with these DNA plasmids by either intramuscular or intradermal injections. RESULTS: The antisera from the immunized mice tested by ELISA showed that only the configuration which had a single copy of universal T helper cell epitope, CS. T3, located at the C terminal of the multi-copy B cell epitopes induced a high antibody response. The T helper cell epitope at any other position of the peptide, or the double T helper cell epitopes configured with the B cell epitopes did not enhance antibody response, and some configurations even decreased the humoral response to a B cell epitope. CONCLUSION: This study demonstrated that both combination and configuration of the epitope may affect the antigenicity of a chimeric multiple antigen.

Animals↗
PubMed2000

[Synthesis of chimeric anti-MDR1 ribozymes (tRNA-Rzs) and their biological activities in cell-free system].

OBJECTIVE: Development of multidrug resistance(MDR) is the major obstacle to successful cancer chemotherapy. One strategy to block the P-glycoprotein(P-gp)-mediated MDR is to use a ribozyme (Rz) target against MDR1 mRNA. METHODS: Three kinds of anti-MDR1 chimeric hammerhead ribozymes, the first-one cleaving codon 196 of MDR1 mRNA (196MDR1-Rz), the second one, a stem-II base modified (U9-->G9, U13-->A13, G14-->A14, A18-->C18) Rz against codon 196 (196MDR1-sRz) and the third one, the stem-II base modified Rz directed against the -6(-)-4 GUC sequence of the translation initiation site of the MDR1 mRNA (iMDR1-sRz), were synthesized based on the cloned retroviral constructs: N2A + tRNAi(met)-196MDR1-Rz, N2A + tRNAi(met)-196MDR1-sRz, N2A + tRNAi(met)-iMDR1-sRz. RESULTS: In a cell-free system, the chimeric tRNA-sRz molecules were more stable and had more efficient catalytic activities than the corresponding naked Rz molecules. The stem-II base modified Rz molecules were also more stable and efficient in catalytic activities than the unmodified ones. In control, the disabled tRNA-mut-iMDR1-sRz had no cleavage activity. CONCLUSION: Base modification in the Rz's stem-II of ribozyme structure and the development of chimeric tRNA-ribozyme molecules are able to enhance the cleavage efficacy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

[Correlation of transplantation tolerance and chimerism induced by allogeneic parabiosis in adult rats].

OBJECTIVE: To induce transplantation tolerance by allogeneic parabiosis in adult rats to explore the relation between chimeras and tolerance. METHODS: Cyclophosphamide (CP, 100 mg/kg) was intraperitonially administered before and after parabiosis to observe the survival days of parabiotic rats. Grafting skin for each other after separation of parabiosed rats pairs on day 5, 15 and 45 respectively to observe the survival time of skin graft survival. In the same time the percentage of cells of donor origin in the spleen and thymus of recipient rats were determined by FACS. Mixed lymphocyte reaction (MLR) and delayed type hypersensivity (DTH) at day 15 of parabiosis were tested. RESULTS: Survival days of parabiotic rats were significantly prolonged (P = 0.000 5, MST = 63.5 days). After 15 day of parabiosis, the stable skin transplantation tolerance was established. During the first 15 day of parabiosis, the level of chimerism was increased with time, afterwards the chimerism became relatively stable. DTH and MLR of parabiotic rats on day 15 were donor-specifically suppressed. CONCLUSION: Parabiosis can induce specific transplantation tolerance in both parabiotic DA and LEW rats. There is a positive correlation of chimerism and transplantation tolerance.

Animals↗
PubMed2002

The perception of emotional chimeric faces in schizophrenia: further evidence of right hemisphere dysfunction.

OBJECTIVE: To examine lateral perceptual bias, an index of right hemisphere function, and its relation to performance on a standard facial perception test and to clinical variables in a large sample of first episode and chronic schizophrenia. BACKGROUND: Judgments made on chimeric faces reliably elicit a perceptual bias to the left hemispace, presumed to be a result of right hemisphere dominance for spatial attention. Recent studies have suggested that this bias is reduced or absent in people with schizophrenia. METHODS: Fifty first-episode and 50 patients with chronic schizophrenic and 50 control subjects were given a brief neuropsychologic battery that included a Happy-Sad Chimeric Face test and the Benton Facial Recognition Test. All patients were rated on the Positive and Negative Syndrome Scale of Schizophrenia after 4 weeks of neuroleptic treatment. All were right handed RESULTS: The patients with schizophrenia showed a significantly weaker perceptual left hemispatial bias compared with controls. In fact the mean bias was in the opposite direction in the chronic group. There was no correlation between left hemispatial bias and either positive or negative symptoms, current medication dose, or mood. Results from the Benton test revealed a performance deficit among the patients with schizophrenia compared with controls but was not correlated with performance on the chimeric faces test in the patients. CONCLUSIONS: The results confirm a specific deficit in right hemisphere attentional functions in schizophrenia, which is separate from a general impairment in facial processing. The deficit is most marked in chronic patients but further study is required to determine whether this is a consequence of prolonged illness.

Adult↗
PubMed2002

Mixed chimerism after bone marrow transplantation for thalassemia major.

Thirty-four thalassemia patients were studied for chimerism by fluorescent in situ hybridization or variable number tandem repeats after bone marrow transplantation. Mixed chimerism was detected in 9 patients with host cells ranging from 4 to 56%. One had graft rejection and the others were transfusion independent. Mixed chimerism was common but mostly without deleterious effect.

Bone Marrow Transplantation↗
PubMed1997

High Expression in Insect Cells of A Functional Chimeric Antibody with Specificity for HBsAg.

We have constructed a double-recombinant virus BacHL4.2 containing both the chimeric heavy- and light-chain cDNAs from monoclonal antibody of the HBsAg gene. Both murine-human chimeric antibody heavy- and light-chain were expressed in Sf9 cells infected with a double-recombinant virus BacHL4.2 or co-infected with separate heavy- and light-chain recombinant viruses. In both cases, expressed products were correctly assembled into normal H(2)L(2) immunoglobulin monomers. ELISA and functional immunoblot assay showed that the recombinant chimeric antibody exhibited a specificity for HBsAg similar to that of the parental murine monoclonal antibody OH3.

Journal Article↗
PubMed2002

[Transient expression of fusion protein with a chimeric HBsAg-HSP70 construct in HepG2 cells].

OBJECTIVE: To investigate transient expression of fusion protein with a chimeric HBsAg-HSP70 construct in HepG2 cells. METHODS: Enkaryotic expression plasmids inserted HBsAg gene or chimeric HBsAg-HSP70 gene were prepared and transfected into HepG2 cells by means of cationic liposome. mRNA were detected by RT-PCR and proteins expressed in the cells were detected by immunocytochemistry 48 hours later. HBsAg in cultured supernatants and cell lysates were assayed by ELISA. RESULTS: Fusion protein (HBsAg-HSP70) transient expression in HepG2 cells were confirmed by RT-PCR, immunocytochemistry or ELISA, but fusion protein was not assayed in cell cultured supernatants by ELISA. CONCLUSIONS: Transfection of HepG2 cells with a chimeric HBsAg-HSP70 construct leads to express fusion protein, but it does not secrete into cell cultured supernatants.

Bacterial Proteins↗