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PubMed1997

Adoptive transfer of in vitro-targeted, activated T lymphocytes results in total tumor regression.

Adoptive immunotherapy of cancer uses the transfer of tumor-reactive immune cells. The success of this procedure is dependent upon the specificity of the transferred immune cells, their number, and their ability to reach their target cells. We genetically modified T lymphocytes and equipped them with the ability to specifically recognize tumor cells. Tumor cells overexpressing the ErbB-2 receptor served as a model. The target cell recognition specificity is conferred to T lymphocytes by transduction of a chimeric gene encoding the zeta-chain of the TCR and a single chain antibody (scFv(FRP5)) directed against the human ErbB-2 receptor. The chimeric scFv(FRP5)-zeta gene was introduced into primary mouse T lymphocytes via retroviral gene transfer. Naive T lymphocytes were activated and infected by cocultivation with a retrovirus-producing packaging cell line. The scFv(FRP5)-zeta fusion gene was expressed in >75% of the T cells. These T cells lysed ErbB-2-expressing target cells in vitro with high specificity. We tested the antitumor efficacy of scFv(FRP5)-zeta-expressing T cells in a syngeneic BALB/c model. The mice were treated with autologous, transduced T cells. The adoptively transferred scFv(FRP5)-zeta-expressing T cells caused total regression of ErbB-2-expressing tumors. The presence of the transduced T lymphocytes in the tumor tissue was monitored. No humoral response directed against the transduced T cells was observed. Abs directed against the ErbB-2 receptor were detected upon tumor lysis.

Animals↗

PubMed1998

Developmental catch-up, and deficit, following adoption after severe global early privation. English and Romanian Adoptees (ERA) Study Team.

The extent of developmental deficit and catch-up following adoption after severe global early privation was examined at 4 years in a sample of 111 Romanian children who came to the U.K. before the age of 2 years, and compared with respect to their functioning at the same age to a sample of 52 U.K. adopted children placed before the age of 6 months. The measures at 4 years included height, head circumference, and general cognitive level (assessed on both the McCarthy and Denver Scales). The children from Romania were severely developmentally impaired at the time of U.K. entry, with about half below the third percentile on height, on weight, on head circumference, and on developmental quotient. Many were also in a poor physical state with recurrent intestinal and respiratory infections. The catch-up in both physical growth and cognitive level appeared nearly complete at 4 years for those children who came to the U.K. before the age of 6 months, despite the fact that their background prior to U.K. entry was similar to the children who came to the U.K. when older. The developmental catch-up was also impressive, but not complete, in those placed after 6 months of age. The mean McCarthy General Cognitive Index was 92 compared with 109 for the within-U.K. adoptees. The strongest predictor of level of cognitive functioning at 4 years was the children's age at entry to the U.K. It was concluded that the remaining cognitive deficit was likely to be a consequence of gross early privation, with psychological privation probably more important than nutritional privation. A further follow-up at age 6 years will determine whether there is continuing recovery after 4 years.

Adoption↗

PubMed1998

Effective adoptive immunotherapy by T-LAK cells retargeted with bacterial superantigen-conjugated antibody to MUC1 in xenografted severe combined immunodeficient mice.

To reinforce cytotoxic activity and the targeting ability of lymphokine-activated killer cells with a T-cell phenotype (T-LAK) for adoptive immunotherapy against human bile duct carcinoma (BDC), staphylococcal enterotoxin A (SEA) was conjugated chemically with MUSE11 monoclonal antibody (MUSE11 mAb), directed to the MUC1 antigen, using N-succinimidyl 3-(2-pyridyldithio) propionate and 2-iminothiolane HCl. Both SEA-conjugated MUSE11 mAb (SEA-MUSE11) and the F(ab')2 of MUSE11 mAb (SEA-F(ab')2) showed significant enhancement of T-LAK cell tumor neutralization for MUC1 positive-target tumor cells, even with a concentration of 0.01 microg/ml at an E:T ratio of 5:1 in vitro. In this in vitro test, MUC1-positive BDC cells were observed to attach to surrounding T-LAK cells in the presence of SEA-MUSE11 or SEA-F(ab')2. Remarkable tumor growth inhibition was observed in BDC-grafted severe combined immunodeficient mice to which 2 x 10(7) T-LAK cells preincubated with 2 microg of SEA-MUSE11 or SEA-F(ab')2, together with recombinant interleukin 2 (500 IU), were administered i.v. for 4 consecutive days, when tumor size was 5 mm in diameter. These results point to a promising adoptive immunotherapy for patients with BDC.

Animals↗

PubMed1998

Long-term neurodevelopmental risks in children exposed in utero to cocaine. The Toronto Adoption Study.

Children exposed in utero to cocaine are at risk for long-term neurobehavioral damage not just because of the drug itself; but also because of clustering of other health determinants, including low socioeconomic status, low maternal education, and maternal addiction, to mention a few. One methodologic approach to separate the direct neurotoxic effects of cocaine from these synergistic insults is to follow up a cohort of children exposed in utero to cocaine and given up for adoption to middle-upper class families. The Toronto Adoption Study, supported by Health Canada, has proven the direct neurotoxic effects of cocaine on IQ and language. These effects are mild to moderate as compared to those measured in children exposed in utero to cocaine and reared by their natural mothers.

Adoption↗

PubMed1998

A three year follow-up of attachment and indiscriminate friendliness in children adopted from Romanian orphanages.

Attachment and indiscriminately friendly behavior were assessed in children who had spent at least 8 months in a Romanian orphanage (RO) and two comparison groups of children: a Canadian-born, nonadopted, never institutionalized comparison group (CB) and an early adopted comparison group adopted from Romania before the age of 4 months (EA). Attachment was assessed using 2 measures: an attachment security questionnaire based on parent report, and a Separation Reunion procedure that was coded using the Preschool Assessment of Attachment. Indiscriminately friendly behavior was examined using parents' responses to 5 questions about their children's behavior with new adults. Although RO children did not score differently from either CB or EA children on the attachment security measure based on parent report, they did display significantly more insecure attachment patterns than did children in the other 2 groups. In addition, RO children displayed significantly more indiscriminately friendly behavior than both CB and EA children, who did not differ in terms of indiscriminate friendliness. RO children's insecure attachment patterns were not associated with any aspect of their institutional environment, but were related to particular child and family characteristics. Specifically, insecure RO children had more behavior problems, scored lower on the Stanford-Binet Intelligence Scale, and had parents who reported significantly more parenting stress than RO children classified as secure.

Adoption↗

PubMed1995

Prolonged disease-free period in patients with advanced epithelial ovarian cancer after adoptive transfer of tumor-infiltrating lymphocytes.

Thirteen patients with epithelial ovarian cancer, who did not show any detectable lesion after cisplatin-containing chemotherapy following primary operation, were treated with adoptive transfer of tumor-infiltrating lymphocytes (TIL group). Eleven patients with almost equivalent conditions of disease, who were treated with only chemotherapy following primary operation, served as a control group. The median time of follow-up was 36 (range, 23-44) months in the TIL group and 33 (range, 14-48) months in the control group. The estimated 3-year overall survival rate of disease-free patients in the TIL group and in the control group was 100% and 67.5%, respectively. A significant difference was noticed between the overall survival rate of the TIL group and the control group (P < 0.01). Furthermore, the estimated 3-year disease-free survival rate of the patients in the TIL group and in the control group was 82.1% and 54.5%, respectively. The disease-free survival rate of patients in the TIL group and in the control group was significantly different (P < 0.05). These results suggest that the adoptive transfer of TILs after all chemotherapy has been finished might be one promising method to achieve complete cure of advanced epithelial ovarian cancer.

Adenocarcinoma↗

PubMed1995

Autologous peripheral blood stem cell transplantation and adoptive immunotherapy with activated natural killer cells in the immediate posttransplant period.

Relapse after high-dose chemotherapy supported by peripheral blood stem cell transplantation (HDC-PBSCT) is the main cause of therapeutic failure in patients with lymphoma and breast cancer. Adoptive immunotherapy with activated natural killer (A-NK) cells and interleukin 2 might eliminate surviving residual tumor without adding to toxicity. Eleven patients with relapsed lymphoma and one with metastatic breast cancer were entered on a pilot clinical trial of HDC-PBSCT followed on day 2 after transplant by infusion of cultured autologous A-NK cells. Simultaneously, recombinant human interleukin 2 (rhIL-2) was initiated as a 4-day continuous i.v. infusion at 2 x 10(6) IU/m2/day, referred to as high-dose rhIL-2. Therapy with high-dose rhIL-2 was followed by a 90-day continuous i. v. infusion at 3 x 10(5) IU/m2/day, referred to as low-dose rhIL-2. All patients engrafted and nine completed treatment. Posttransplant days to a neutrophil count of 500/microliter and to a platelet count of 50,000/microliter were similar to comparable patients treated with HDC-PBSCT alone. Generation of A-NK cells for therapy was feasible in all patients except the three patients with Hodgkin's disease, whose cells did not proliferate in culture. Overall toxicity associated with early posttransplant transfer of A-NK cells and interleukin 2 did not differ from that observed with peripheral blood stem cell transplantation alone in comparable patients. There was early amplification of natural killer cell activity in the peripheral blood of four patients that appeared to result from the transfused A-NK cells. Adoptive transfer of A-NK cells and rhIL-2 during the pancytopenic phase after HDC-PBSCT was feasible and well tolerated, did not adversely affect engraftment, and resulted in amplified natural killer activity in the peripheral blood during the immediate posttransplantation period.

Adoptive Transfer↗

PubMed1999

Adoptive T-cell therapy.

Adoptive immunotherapy, or the transfer of immunocompetent cells, has been shown to be a promising new strategy for treatment of a variety of malignancies, including leukemia and non-Hodgkin's lymphoma. The possibility that it may likewise benefit patients with multiple myeloma is now being explored by researchers in Europe and the United States. Two alternatives, one using donor leukocyte infusions (DLIs) and the other using autologous T cells, are described. In the Netherlands, researchers studied the use of DLIs in 17 patients with multiple myeloma who relapsed after bone marrow transplant (BMT). Of 16 evaluable patients, 10 (62%) responded, with six (37%) achieving a complete response (CR). After a median follow-up duration of 28 months, five patients relapsed and five remained in remission. Graft-versus-host disease (GVHD) developed in nine patients. In the United States, adoptive immunotherapy is currently being tested in eight patients with chemotherapy-resistant lymphoma. Autologous T cells were obtained prior to BMT and expanded using an anti-CD3/CD28 culture system. After BMT, the cells were reinfused into the patient. At approximately day 14, granulocyte levels began to recover in the six evaluable patients, and levels remained relatively stable over the posttreatment course. Two patients developed severe autoimmune toxicity, which responded to treatment in one and resolved spontaneously in the other.

Humans↗

PubMed1978

MMPI assessment of psychopathology in the adopted-away offspring of schizophrenics.

Previous studies completed in Denmark show a higher frequency of schizophrenia-related psychopathology in the adopted offspring of schizophrenics than in matched controls. This study adds a psychometric dimension to the earlier reports with an analysis of psychopathology in the adopted offspring of schizophrenics based on the Minnesota Multiphasic Personality Inventory (MMPI). A combination of MMPI criteria and interview-based diagnosis identifies 22% of the index cases and 6% of the control cases (P less than .01) as having a schizophrenia spectrum disorder. The findings support a genetic hypothesis, but the use of the MMPI does not fully clarify some issues raised in the earlier reports.

Adult↗

PubMed1996

Encouraging small businesses to adopt effective technologies to prevent exposure to health hazards.

Small businesses are heterogeneous and the prospects are low for direct OSHA inspection and enforcement. Opportunities are explored to encourage voluntary adoption of new technology to reduce workplace exposures. The case of radiator repair shops is used in this paper to illustrate an approach to the dissemination of control technology to small businesses that will encourage these companies to adopt controls. Several behavioral theories are applied to the case.

Automobiles↗

PubMed2000

Predominant torsional forms adopted by dipeptide conformers in solution: parameters for molecular recognition.

The present paper describes the predominant conformational forms adopted by dipeptides in aqueous solution. More than 50 dipeptides were subjected to conformational analysis using SYBYL Random Search. The resultant collections of conformers for individual dipeptides, for small groups with related side chain residues and for large groups of about 50 dipeptides were visualized graphically and analysed using a novel three-dimensional pseudo-Ramachandran plot. The distribution of conformers, weighted according to the percentage of each in the total conformer pool, was found to be restricted to nine main combinations of backbone psi (psi) and phi (phi) torsion angles. The preferred psi values were in sectors A7 (+150 degrees to +/-180 degrees), A10 (+60 degrees to +90 degrees) and A4 (-60 degrees to -90 degrees), and these were combined with preferred phi values in sectors B12 (-150 degrees to +/-180 degrees), B9 (-60 degrees to -90 degrees) and B2 (+30 degrees to +60 degrees). These combinations of psi and phi values are distinct from those found in common secondary structures of proteins. These results show that although dipeptides can each adopt many conformations in solution, each possesses a profile of common conformers that is quantifiable. A similarly weighted distribution of dipeptide conformers according to distance between amino-terminal nitrogen and carboxyl-terminal carbon shows how the preferred combinations of backbone torsional angles result in particular N-C geometries for the conformers. This approach gives insight into the important conformational parameters of dipeptides that provide the basis for their molecular recognition as substrates by widely distributed peptide transporters. It offers a basis for the rational design of peptide-based bioactive compounds able to exploit these transporters for targeting and delivery.

Computer Simulation↗

PubMed1985

Clinical response of a patient with diffuse histiocytic lymphoma to adoptive chemoimmunotherapy using cyclophosphamide and alloactivated haploidentical lymphocytes. A case report and phase I trial.

Adoptive chemoimmunotherapy has cured experimentally induced tumors in animals, but its clinical use has been limited. Six patients were treated with refractory neoplasms in a Phase I study with cyclophosphamide (CPM) and alloactivated haploidentical lymphocytes. Patients received an immunosuppressive dose of CPM (800 mg/m2) followed by haploidentical lymphocytes primed in vitro with alloantigens in mixed lymphocyte culture (MLC). One week later patients received a second infusion of alloactivated lymphocytes expanded in T-cell growth factor (TCGF). The total number of cells given to each patient progressively increased, with a single patient receiving 35.5 X 10(9) cells. Transient febrile responses and delayed-type hypersensitivity reactions at the intravenous sites were the only toxicities noted. A complete clinical response lasting 12 weeks was seen in a single patient with diffuse histiocytic lymphoma. Our experience indicates that adoptive chemoimmunotherapy can be given to patients safely and merits further clinical testing.

Blood Transfusion↗

PubMed1988

Cancer prevention and detection. An overview of variables influencing adoption and practice.

This paper presents an overview of factors, attitudes, and beliefs that may influence the adoption of cancer prevention and detection strategies by health-care providers and the public. Health-care practitioners require education about prevention and detection approaches to health care and the social variations in the population that may influence acceptance and adoption of these measures. The need for consistent guidelines among health professional organizations is also stressed.

Attitude of Health Personnel↗

PubMed1988

Adoptive immunotherapy for recurrent glioblastoma multiforme using lymphokine activated killer cells and recombinant interleukin-2.

Thirteen patients with recurrent glioblastoma were treated with adoptively transferred autologous lymphokine activated killer (LAK) cells and recombinant interleukin-2 (rIL-2). Patients' blood mononuclear cells (MNC) obtained by leukapheresis were cultured at 2.5 million MNC per ml for 3 to 5 days in media containing 1000 U rIL-2/ml. After incubation, the nonadherent MNC from all cultures (0.5-5 X 10(9] were combined and concentrated for infusion in 5 to 10 ml saline containing 10(6) U rIL-2. Nine patients received one injection of LAK cells and rIL-2 into the brain tissue immediately surrounding the tumor cavity during craniotomy for subtotal tumor removal (Group 1). On each of the 3 days after surgery, patients received boosters of 10(6) U rIL-2 delivered into the tumor cavity through a skin flap or via an Ommaya reservoir. Approximately 1 to 2 weeks after this series of injections, these patients were treated with a second cycle of LAK cells and rIL-2 injected into the tumor cavity using the reservoir. Four patients received both adoptive immunotherapy cycles by intracavitary injection (Group 2). In this relatively small patient pool, neither age, sex, Karnofsky score, treatment history, nor anticonvulsant and steroid dosage appeared to influence a patient's ability to make LAK cells. The therapy, itself, was well-tolerated by all patients although they all displayed symptoms of aseptic meningitis and increased intracranial pressure, i.e., headache, fever, malaise on the days of LAK cell and/or rIL-2 infusion. The therapy did not appear to have a significant impact on patient survival (mean, 30 weeks) especially for those patients with a high postsurgical tumor burden. As the therapy is safe, the authors believe its efficacy can best be tested in patients with a newly diagnosed or recurrent glioblastoma which lies in an area where a near-total resection is possible.

Adult↗

PubMed1990

Proteoglycan-induced polyarthritis and spondylitis adoptively transferred to naive (nonimmunized) BALB/c mice.

Mononuclear cells from BALB/c mice with progressive polyarthritis and spondylitis induced by injection of fetal human articular cartilage proteoglycan (PG) were used to transfer arthritis by intravenous injection into irradiated, nonimmunized syngeneic mice. Successful transfer of arthritis to BALB/c mice required the injection of lymphocytes from mice with arthritis, along with 50 micrograms of human fetal PG, or lymphocytes stimulated in vitro with either fetal human PG or with mouse cartilage PG. In addition, interleukin-2 or immune sera from animals with arthritis significantly reduced the time to onset of transferred disease. The onset of adoptively transferred arthritis, using cells and antigen, from the time of the first injection (38.2 +/- 18.2 days, mean +/- SD) was shortened if lymphocytes from mice with transferred arthritis were reinjected (retransferred) into other, irradiated syngeneic mice (6.1 +/- 2.6 days). The appearance of autoreactive antibodies to mouse cartilage PG in the sera of mice with adoptively transferred arthritis (secondary or tertiary) preceded the appearance of the first clinical symptoms by a few days. The transfer of arthritis was blocked by pretreatment of donor (arthritic) lymphocytes with either anti-T cell or anti-B cell antibodies and complement. Exposure of mononuclear cells from mice with arthritis to PG, and its removal prior to transfer, also resulted in transfer of the arthritis. PG-induced arthritis was not transferred to nonirradiated mice, nor to irradiated mice injected with lymphocytes from animals with primary arthritis without chondroitinase ABC-digested fetal human PG. Arthritis never developed after injection of immune sera from mice with arthritis (without cells), nor when cells of nonarthritic animals were used with chondroitinase ABC-digested fetal human PG, with or without interleukin-2.

Animals↗

PubMed1991

Down-regulation of adoptive adjuvant-induced arthritis by suppressor factor(s).

We recently described a method for inducing immunologic tolerance to trinitrochlorobenzene (TNCB), a hapten that generates suppressor cells capable of down-regulating the efferent phase of TNP-specific contact hypersensitivity in rats. Peritoneal exudate cells (PEC) of such tolerized rats, upon being triggered by specific hapten, suppressed contact hypersensitivity to another hapten elicited at the same time. This implied that cells that mediate delayed-type hypersensitivity of any specificity might be down-regulated, provided that the suppressor cells are activated with specific antigen and that the unrelated delayed-type hypersensitivity is elicited in parallel. To rigorously test this possibility, we examined the ability of TNP-specific suppressor lymphoid cell factors to affect cells that mediate adoptively transferable adjuvant-induced arthritis (AIA) in rats. To induce arthritis, spleen cells from Freund's complete adjuvant-injected rats were stimulated with concanavalin A and administered to naive recipients. Prior to adoptive transfer, the cells were exposed for brief intervals to supernatants of lymphoid cells from control and hapten-tolerized rats. Supernatants of PEC and lymph node cells from hapten-tolerized rats were found to markedly reduce the effectiveness of cells that mediate AIA. The hapten-tolerized cells required reexposure to hapten prior to preparation of the supernatants. Supernatants of spleen cells from hapten-tolerized rats that had been hapten-painted as well as hapten-triggered and supernatants of lymph node cells and of PEC from only hapten-painted or hapten-triggered rats were ineffective in altering the AIA. Thus, factors from suppressor cells induced toward hapten-coupled self-antigens have been found to adversely affect the function of lymphoid cells that mediate a totally unrelated inflammatory response, namely, AIA. The clinical implications of these findings are discussed.

Animals↗

PubMed2007

Assessing immunophenotyping performance: proficiency-validation for adopting improved flow cytometry methods.

BACKGROUND: The continuous improvement and evolution of immune cell phenotyping requires periodic upgrading of laboratory methods and technology. Flow cytometry laboratories that are participating in research protocols sponsored by the NIAID are required to perform "switch" studies to validate performance before methods for T-cell subset analysis can be changed. METHODS: Switch studies were conducted among the four flow cytometry laboratories of the Multicenter AIDS Cohort Study (MACS), comparing a 2-color, lyse-wash method and a newer, 3-color, lyse no-wash method. Two of the laboratories twice failed to satisfy the criteria for acceptable differences from the previous method. Rather than repeating more switch studies, these laboratories were allowed to adopt the 3-color, lyse no-wash method. To evaluate the impact of the switch to the new method at these two sites, their results with the new method were evaluated within the context of all laboratories participating in the NIH-NIAID-Division of AIDS Immunology Quality Assurance (IQA) proficiency-testing program. RESULTS: Laboratory performance at these two sites substantially improved relative to the IQA standard test results. Variation across the four MACS sites and across replicate samples was also reduced. CONCLUSIONS: Although switch studies are the conventional method for assessing comparability of laboratory methods, two alternatives to the requirement of repeating failed switch studies should be considered: (1) test the new method and assess performance on the proficiency testing reference panel, and (2) prior to adoption of the new methods, use both the old and the new method on the reference panel samples and demonstrate that performance with the new method is better according to standard statistical procedures. These alternatives may help some laboratories' transition to a new and superior methodology more quickly than if they are required to attempt multiple, serial switch studies.

Acquired Immunodeficiency Syndrome↗

PubMed1990

Adoptive transfer of fluorescence-labeled cells shows that resident peritoneal macrophages are able to migrate into specialized lymphoid organs and inflammatory sites in the mouse.

We have examined the migration of murine macrophages from the vascular compartment to normal and inflammatory tissues by the adoptive transfer of resident peritoneal macrophages (RPM phi) fluorescently labeled with the hydrophobic dye 1,1'-dioctadecyl 3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI). After initial labeling of the plasma membrane of RPM phi, the dye accumulated stably in intracellular vesicles of low density (rho = 1.042-1.045 kg/l) and cells remained viable in culture for 4 weeks. Like the normal monocyte, DiI-RPM phi, but not exudate-derived or fixed cells, migrated to peritoneal exudates, following i.v. adoptive transfer, by a mechanism inhibitable by an antibody to the type 3 complement receptor. In the absence of an inflammatory stimulus there was no migration to the peritoneal cavity, and DiI-RPM phi accumulated within 4 h in the red pulp and marginal zone of the spleen. By day 6 these cells still formed a tight ring of fluorescence in the marginal zone alone, outside the marginal metallophil cells. DiI-RPM phi injected into the peritoneal cavity migrated to the parathymic lymph nodes where they were found in the subcapsular sinus and in the medullary cords, whereas very few fluorescent cells could be found in the T cell areas. The migration of RPM phi to lymphoid organs required viable cells but, unlike the recruitment of cells to peritoneal exudates, was not inhibitable by antibodies to CR3. We conclude that the RPM phi is a useful surrogate for the analysis of constitutive and induced monocyte migration to secondary lymphoid and inflammatory sites, respectively.

Animals↗