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PubMed1993

Antitumor effects of interleukin-7 and adoptive immunotherapy on human colon carcinoma xenografts.

The antitumor properties of recombinant human IL-7 (rhIL-7) on a human tumor was evaluated by engrafting a human colon carcinoma into immunodeficient mice and then treating the mice with rhIL-7 and adoptively transferred human peripheral blood T cells. It was found that rhIL-7 alone had no effect on the survival of the tumor-bearing recipients. However, the combination of rhIL-7 and human T cells significantly promoted the survival of the recipients compared with mice receiving either treatment by itself. When the surviving mice were analyzed 6 mo later for the degree of human cell engraftment, the recipients receiving both rhIL-7 and human T cells had greater numbers of human CD8+ T cells in the spleens. However, the human T cells recovered from the surviving mice showed low lytic activity against the tumor in vitro. Supernatants from human T cells cultured with the tumor and rhIL-7 in vitro were found to inhibit tumor growth and were demonstrated to contain high levels of IFN-gamma. Antibodies to IFN-gamma neutralized the growth inhibition of the tumor both in vitro and in vivo demonstrating that the in vivo mechanism underlying the antitumor effects of this regimen was partly dependent on the production of IFN-gamma by the T cells and not their cytolytic capability. Interestingly, systemic administration of rhIFN-gamma to tumor-bearing mice yielded little antitumor effect suggesting that adoptive immunotherapy with rhIL-7 was superior possibly because of the continuous local release of the cytokines. Therefore, rhIL-7 may be of clinical use as an antineoplastic agent and the human/mouse model is a potentially important preclinical model for in vivo evaluation of the efficacy of this and other immunotherapies.

Animals↗
PubMed1994

The pathogenesis of adoptive murine autoimmune diabetes requires an interaction between alpha 4-integrins and vascular cell adhesion molecule-1.

An adoptive transfer model of insulin-dependent diabetes mellitus (IDDM) in the nonobese diabetic mouse was used to examine the roles of alpha 4-integrin, vascular cell adhesion molecule 1 (VCAM-1); and intercellular adhesion molecule 1 (ICAM-1) in the pathogenesis of autoimmune diabetes. Antibodies specific for both alpha 4-integrin and one of its ligands, VCAM-1, were able to delay onset of diabetes and decrease the incidence of the disease in adoptive transfer studies. This blocking of disease was accompanied by a marked decrease in lymphocytic infiltration of the islets of Langerhans. Furthermore, these antibodies preferentially block entrance of CD4 T cells into the tissue. Antibodies specific for ICAM-1 had little effect on the onset or incidence of IDDM. Thus, we conclude that an alpha 4-integrin-VCAM-1 interaction is important in T cell entry into the islets of Langerhans and in the pathogenesis of IDDM. In addition, the cascade of events leading to T cell transit across endothelium may be different for CD4 and CD8 cells, and may differ depending on the endothelium involved. Our results support the more general conclusion that an alpha 4-integrin-VCAM-1 interaction may be crucial in allowing activated effector CD4T cells to leave the blood and enter tissue to clear infection.

Animals↗
PubMed1996

Prevention of adoptively transferred diabetes in nonobese diabetic mice with IL-10-transduced islet-specific Th1 lymphocytes. A gene therapy model for autoimmune diabetes.

Four pancreatic islet-specific CD4+ helper T (Th) 1 (Th1) clones and two Th1 clones transduced with an SRalpha promoter-linked murine IL-10 (mIL-10) cDNA of 2.0-6.0 x 10(6) cells were adoptively transferred to nonobese diabetic (NOD) mice at age 8 d. Cyclophosphamide (CY) was administered at age 37 d (plus CY), and the incidence of diabetes and the histological grade of insulitis were examined at age 47 d. After the adoptive transfer of IL-10-transduced Th1 cells, polymerase chain reaction (PCR) and reverse-transcription (RT)-PCR detected the neo gene and the retrovirus vector-mediated IL-10 mRNA in situ in recipient islets, respectively. RT-PCR detected the decrease of IFN-gamma mRNA relative to IL-10 mRNA in IL-10-transduced Th1 clones in vitro and also in recipient islets. All four wild type Th1 clones plus CY induced the insulitis grade of 2.75 and diabetes in 66% of recipient NOD mice. IL-10-transduced two Th1 clones plus CY induced periinsulitis with the grade of 1.43 and diabetes in 8.0%. The 1:1 mixture of wild type Th1 cells and IL-10-transduced Th1 cells plus CY induced periinsulitis with the grade of 1.85 and diabetes in 20%. The suppression of diabetes through decreasing IFN-gamma mRNA by the tissue-specific delivery of IL-10 to pancreatic islets with IL-10-transduced Th1 cells affords us the starting basis to develop the gene therapy for autoimmune diabetes.

Adoptive Transfer↗
PubMed1997

CD40-activated human B cells: an alternative source of highly efficient antigen presenting cells to generate autologous antigen-specific T cells for adoptive immunotherapy.

Multiple clinical trials have shown the efficacy of adoptively transferred allogeneic antigen-specific T cells for the treatment of viral infections and relapsed hematologic malignancies. In contrast, the therapeutic potential of autologous antigen-specific T cells has yet to be established since it has been technically difficult to generate sufficient numbers of these T cells, ex vivo. A major obstacle to the success of this objective derives from our inability to simply and rapidly isolate and/or expand large numbers of highly efficient antigen presenting cells (APCs) for repetitive stimulations of antigen-specific T cells in vitro. We show that autologous CD40-activated B cells represent a readily available source of highly efficient APC that appear to have several important advantages over other APCs for ex vivo T cell expansion including: (a) methodological simplicity necessary to generate continuously large numbers of APCs from just 50 cm3 of peripheral blood without loss of APC function; (b) capacity to induce high peak T cell proliferation and interferon-gamma production without IL-10 production; (c) ease in cryopreservation; and (d) markedly reduced cost. We, therefore, contend that CD40-activated B cells are an alternative source of highly efficient APCs with which to generate antigen-specific T cells ex vivo for autologous adoptive immunotherapy.

3T3 Cells↗
PubMed2005

Renal allograft rejection is prevented by adoptive transfer of anergic T cells in nonhuman primates.

Anergic T cells generated ex vivo are reported to have immunosuppressive effects in vitro and in vivo. Here, we tested this concept in nonhuman primates. Alloreactive T cells were rendered anergic ex vivo by coculture with donor alloantigen in the presence of anti-CD80/CD86 mAbs before adoptive transfer via renal allograft to rhesus monkey recipients. The recipients were briefly treated with cyclophosphamide and cyclosporine A during the preparation of the anergic cells. Thirteen days after renal transplantation, the anergic T cells were transferred to the recipient, after which no further immunosuppressive agents were administered. Rejection-free survival was prolonged in all treated recipients, and 3 of 6 animals survived long term (410-880 days at study's end). In the long-surviving recipients, proliferative responses against alloantigen were inhibited in a donor-specific manner, and donor-type, but not third-party, skin allografts were also accepted, which demonstrated that antigen-specific tolerance had been induced. We conclude that anergic T cells generated ex vivo by blocking CD28/B7 costimulation can suppress renal allograft rejection after adoptive transfer in nonhuman primates. This strategy may be applicable to the design of safe clinical trials in humans.

Adoptive Transfer↗
PubMed2005

Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CD8+ T cells.

T cell differentiation is a progressive process characterized by phenotypic and functional changes. By transferring tumor-specific CD8+ T cells into tumor-bearing mice at various stages of differentiation, we evaluated their efficacy for adoptive immunotherapy. We found that administration of naive and early effector T cells, in combination with active immunization and IL-2, resulted in the eradication of large, established tumors. Despite enhanced in vitro antitumor properties, more-differentiated effector T cells were less effective for in vivo tumor treatment. Several events may underlie this paradoxical phenomenon: (a) downregulation of lymphoid-homing and costimulatory molecules; (b) inability to produce IL-2 and access homeostatic cytokines; and (c) entry into a proapoptotic and replicative senescent state. While the progressive acquisition of terminal effector properties is characterized by pronounced in vitro tumor killing, in vivo T cell activation, proliferation, and survival are progressively impaired. These findings suggest that the current methodology for selecting T cells for transfer is inadequate and provide new criteria for the generation and the screening of optimal lymphocyte populations for adoptive immunotherapy.

Animals↗
PubMed2005

Toward improved immunocompetence of adoptively transferred CD8+ T cells.

Adoptive transfer of autologous or allogenic T cells to patients is being used with increased frequency as a therapy for infectious diseases and cancer. However, many questions remain with regard to defining optimized procedures for preparation and selection of T cell populations for transfer. In a new study in this issue of the JCI, Gattinoni and colleagues used a TCR transgenic mouse model to examine in vitro-generated tumor antigen-specific CD8+ T cells at various stages of differentiation for their efficacy in adoptive immunotherapy against transplantable melanoma. The results confirm that CD8+ T cells progressively lose immunocompetence with prolonged in vitro cultivation and suggest that effector CD8+ T cells alone may be considerably less potent at protecting hosts with advanced tumors than are less differentiated T cells.

Animals↗
PubMed1983

Critique of the Danish-American studies of the biological and adoptive relatives of adoptees who became schizophrenic.

The authors present various reasons why their analysis of the data provided by the Danish-American studies of the relatives of adoptees who became schizophrenic demonstrates that the data do not support the investigators' claims that their studies provide conclusive evidence of a significant genetic factor in the etiology of schizophrenia. When taken together with the authors' earlier demonstration that the investigators' more direct study of the adopted-away offspring of schizophrenic parents failed to provide statistically significant evidence of a genetic influence, these adoption studies indicate that although genetic factors may play some role in the etiology of chronic schizophrenic disorders, such findings are far from definite or proven.

Adoption↗
PubMed1983

Adoption and disturbed narcissism: a case illustration of a latency boy.

The analysis of a latency-age boy, adopted at birth, is presented. Clinical material, particularly having to do with family romance fantasies created by the patient to account for why the biological parents "got rid of" him, are focused upon. The relation between being adopted and disturbed narcissism is considered.

Adoption↗
PubMed1995

Gender identity disorder in a girl: insights from adoption.

Gender identity disorder in girls is reported far less frequently than in boys. The analysis of a six-year-old adopted girl with gender identity disorder is presented to show the importance of the mother-infant relationship and of parental, especially maternal, attitudes toward gender in the normal development of gender identity and gender role definition. This child's unusual history included a late adoption, with clear evidence of separation trauma, and the ongoing influence of maternal infertility. Her symptoms of gender identity disorder appeared before her second birthday and were well established by three years of age. The analysis, from age six to thirteen, achieved a better adaptation to her gender. Her masculine strivings gradually became incorporated into an essentially feminine orientation.

Adolescent↗
PubMed1989

Frequency of adoption of children and adolescents with learning disabilities.

Students from three different facilities who were diagnosed as learning disabled were studied to determine the frequency of adoption with this population as compared to the national norm. The frequency of adoption was found to be 4.5 times higher than the norm, that is, 17.3% versus 3.9%. The possible reasons for this high incidence are discussed.

Adolescent↗
PubMedDate not supplied

Liver metastases from gastric carcinoma: report of a patient treated with adoptive immunotherapy (tumor-infiltrating lymphocytes plus interleukin-2 and subsequently local-regional lymphokine-activated killer cells plus interleukin-2).

A 37-year-old patient with liver metastases from gastric cancer was treated with a double adoptive immunotherapy regimen comprising tumor-infiltrating lymphocytes plus interleukin-2 and subsequently local-regional lymphokine-activated killer cells plus interleukin-2 because of an extremely high in vitro cytotoxic specific activity on established gastric cancer cell lines. The necrosis verified in the center of the hepatic metastasis would appear to demonstrate treatment efficacy, but no clinical response was seen. In vitro cytotoxicity data alone are insufficient to predict the clinical efficacy of adoptive immunotherapy.

Adult↗
PubMed1986

Overrepresentation of adopted children attending a children's mental health centre.

A retrospective analysis was made of case records of children attending a Children's Mental Health Centre during the years 1959 to 1973. Annual comparisons were made between the numbers of adopted children seen in the province of Ontario and within the clinic setting. The results indicated that over a fifteen year period the adopted children in the clinic were seen with twice the expected annual incidence predicted from the community rates.

Adolescent↗
PubMed1999

Induced lactation in an adoptive mother.

This case report describes the experiences of an gravida 3 para 0 adoptive mother who initiated the use of bilateral pumping, metoclopramide, syntocinon nasal spray, and a supplemental nursing system to induce lactation. Lactogenesis was initiated within 10 days of the adoption. No measurable milk was pumped until the baby was 4 months old at which time the mother began pumping 4 ounces per breast within 1 week. The mother stopped pumping, taking metoclopramide (Regian) and syntocinon, and using the supplementer system at this time. She continued to breastfeed without the use of bottles throughout the fourth and fifth months with the baby maintaining adequate weight gain.

Adaptation, Psychological↗
PubMed1992

A 9L gliosarcoma transplantation model for studying adoptive immunotherapy into the brains of conscious rats.

A rat model for brain tumor immunotherapy is described that closely mimics the type of treatment that could be administered to humans. It involves surgical implantation of a permanent cannula in the brain, through which tumor cells and various effector cells and/or cytokines can be injected. The advantage of this system over more conventional animal surgical procedures is that conscious animals can be treated multiple times while avoiding morbidity and mortality associated with reoperative procedures. Using this system to study adoptive immunotherapy for brain tumors, we provide evidence that the 9L gliosarcoma tumor from the Fischer rat strain can be reduced or destroyed in situ following adoptive immunotherapy with specifically activated cytotoxic T lymphocytes.

Animals↗
PubMed2007

Is the adoption and safe families act influencing child welfare outcomes for families with substance abuse issues?

The Adoption and Safe Families Act (ASFA) was designed to promote more timely permanent placements for children in the child welfare system. To date, however, available data have said little about whether ASFA is meeting its intended goals. This study looks at the impact of ASFA on parents struggling with substance abuse issues. The authors compared child welfare outcomes, pre- and post-ASFA, for children of more than 1,900 substance-abusing women with some treatment involvement. After the implementation of ASFA, children in this study spent less time in foster care, were placed in permanent settings more quickly, and were more likely to be adopted than remain in long-term foster care. The proportion of children who were reunified with their parent or parents stayed the same. These outcomes were apparent even controlling for case and family characteristics. Results are discussed in terms of the influence of ASFA on service delivery systems.

Adoption↗
PubMed2002

Generating CTLs against the subdominant Epstein-Barr virus LMP1 antigen for the adoptive immunotherapy of EBV-associated malignancies.

The Epstein-Barr virus (EBV)-encoded LMP1 protein is expressed in EBV-positive Hodgkin disease and is a potential target for cytotoxic T-lymphocyte (CTL) therapy. However, the LMP1-specific CTL frequency is low, and so far the generation of LMP1-specific CTLs has required T-cell cloning. The toxicity of LMP1 has prevented the use of dendritic cells (DCs) for CTL stimulation, and we reasoned that an inactive, nontoxic LMP1 mutant (DeltaLMP1) could be expressed in DCs and would enable the activation and expansion of polyclonal LMP1-specific CTLs. Recombinant adenoviral vectors expressing LMP1 or DeltaLMP1 were tested for their ability to transduce DCs. LMP1 expression was toxic within 48 hours whereas high levels of DeltaLMP1 expression were achieved with minimal toxicity. DeltaLMP1-expressing DCs were able to reactivate and expand LMP1-specific CTLs from 3 healthy EBV-seropositive donors. LMP1-specific T cells were detected by interferon-gamma (IFN-gamma) enzyme-linked immunospot assay (ELISPOT) assays using the HLA-A2-restricted LMP1 peptide, YLQQNWWTL (YLQ). YLQ-specific T cells were undetectable (less than 0.001%) in donor peripheral blood mononuclear cells (PBMCs); however, after stimulation the frequency increased to 0.5% to 3.8%. Lysis of autologous target cells by CTLs was dependent on the level of LMP1 expression. In contrast, the frequency of YLQ-specific CTLs in EBV-specific CTLs reactivated and expanded using lymphoblastoid cell lines was low and no LMP1-specific cytotoxic activity was observed. Thus, DeltaLMP1 expression in DCs is nontoxic and enables the generation of LMP1-specific CTLs for future adoptive immunotherapy protocols for patients with LMP1-positive malignancies such as EBV-positive Hodgkin disease. Targeting LMP1 in these malignancies may improve the efficacy of current adoptive immunotherapy approaches.

Adenoviruses, Human↗
PubMed2005

Adoptive transfer of gene-engineered CD4+ helper T cells induces potent primary and secondary tumor rejection.

Because CD4+ T cells play a key role in aiding cellular immune responses, we wanted to assess whether increasing numbers of gene-engineered antigen-restricted CD4+ T cells could enhance an antitumor response mediated by similarly gene-engineered CD8+ T cells. In this study, we have used retroviral transduction to generate erbB2-reactive mouse T-cell populations composed of various proportions of CD4+ and CD8+ cells and then determined the antitumor reactivity of these mixtures. Gene-modified CD4+ and CD8+ T cells were shown to specifically secrete Tc1 (T cytotoxic-1) or Tc2 cytokines, proliferate, and lyse erbB2+ tumor targets following antigen ligation in vitro. In adoptive transfer experiments using severe combined immunodeficient (scid) mice, we demonstrated that injection of equivalent numbers of antigen-specific engineered CD8+ and CD4+ T cells led to significant improvement in survival of mice bearing established lung metastases compared with transfer of unfractionated (largely CD8+) engineered T cells. Transferred CD4+ T cells had to be antigen-specific (not just activated) and secrete interferon gamma (IFN-gamma) to potentiate the antitumor effect. Importantly, antitumor responses in these mice correlated with localization and persistence of gene-engineered T cells at the tumor site. Strikingly, mice that survived primary tumor challenge could reject a subsequent rechallenge. Overall, this study has highlighted the therapeutic potential of using combined transfer of antigen-specific gene-modified CD8+ and CD4+ T cells to significantly enhance T-cell adoptive transfer strategies for cancer therapy.

Adoptive Transfer↗