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PubMed2003

Rapid, large-scale generation of highly pure cytomegalovirus-specific cytotoxic T cells for adoptive immunotherapy.

Adoptive transfer of donor-derived cytomegalovirus (CMV)-specific cytotoxic T cell (CTL) clones can restore immunity in allogeneic stem cell transplant recipients, providing protection against CMV disease. Current methods for selecting and expanding CMV-specific T cell clones are technically difficult, making adoptive T cell therapy impractical for routine clinical use. In this study, we describe a method for ex vivo generation and expansion of high-purity CMV-specific CTL using peptide-pulsed dendritic cells as antigen-presenting cells. Generation of CMV-specific CTL in numbers sufficient for clinical use in the time span of 4 weeks was accomplished in 6 of 8 CMV-seropositive donors. Examination of pp65 specificity by HLA/peptide tetramer staining demonstrated that a purity of greater than 95% peptide-specific cells could be obtained after two weekly stimulations and retained after further expansion for 3-4 weeks. Median expansion of total cell number was greater than 500-fold and expansion of peptide-specific CTL by tetramer staining was greater than 1.7 x 10(5)-fold. Four weeks after initiating CTL culture, we were able to generate greater than 10(9) total cells that specifically lysed target cells loaded with CMV peptide and cells infected with CMV. This simple and rapid method for generating high-purity CMV-specific CTL for adoptive immunotherapy is currently being examined for routine clinical use for allogeneic stem cell transplantation.

Antigen-Presenting Cells↗
PubMed2006

A survey of the health, sleep, and development of children adopted from China.

The health, development, and sleeping patterns of 240 children adopted from China were examined using a survey research approach. Eighty percent of the children were 18 months of age or younger when adopted, and 98 percent of the children were girls. Sixty-two percent of the children were reported to have been developmentally delayed at the time of adoption; of this number, 91 percent were reported to have had delays in motor development. Of the families, 52 percent reported that children experienced sleep problems, but only 9 percent of the total sample experienced significant sleep difficulties. Implications for social workers are also discussed.

Adoption↗
PubMed1991

Limitations of the adoptive immunity assay for analyzing anti-Listeria immunity.

The usefulness of adoptive immunization as a method for analyzing mechanisms responsible for resolution of Listeria monocytogenes infection was studied. Results showed that, although mice resolving primary infection acquire CD8+ T cells that are exclusively capable of adoptively immunizing recipient mice against an L. monocytogenes challenge infection, these T cells are protective only if given to recipients at very early stages of infection (soon after the infection is cleared from the blood by fixed phagocytes of the liver and spleen). In contrast the same T cells failed to mediate adoptive immunity against infection if given to recipients 24 h after infection was initiated, when L. monocytogenes is no longer in fixed phagocytes but is confined to granulomas. These results indicate that specific CD8+ T cells produced in response to infection contribute minimally to resolution of established infection in the donor.

Animals↗
PubMed1995

Tumor antigen-specific immunization of bone marrow transplantation donors as adoptive therapy against established tumor.

BACKGROUND: Persistence of the underlying malignancy remains the main obstacle to the successful treatment of human malignancies with high-dose chemoradiotherapy and bone marrow transplantation. PURPOSE: The aim of this study was to determine whether antigen-specific antitumor immune responses, elicited in normal donor mice by immunization with the soluble form of a surrogate tumor antigen (i.e., ovalbumin [OVA]), can be transferred via bone marrow transplantation into lethally irradiated, syngeneic recipient mice. An additional goal was to evaluate the ability of these adoptively transferred bone marrow cells to eradicate established recombinant OVA-expressing lymphomas that recurred after lethal-dose total-body irradiation (TBI). METHODS: Female C57BL/6 donor mice were immunized twice with OVA emulsified in a muramyl-dipeptide-containing adjuvant. Syngeneic mice bearing a day-10 or day-11, approximately 1-cm subcutaneous E.G7-OVA tumor (E.G7-OVA tumor cells were derived from transfection of EL-4 thymoma tumor cells using the coding sequence of chicken OVA gene complementary DNA) were treated with TBI and reconstituted with bone marrow from nonimmune or OVA-immunized mice. In subsequent experiments, tumor-bearing mice, treated with TBI and OVA-immune bone marrow, were given additional therapy either with a single OVA immunization or by the adoptive transfer of 1 x 10(7) in vitro activated spleen cells derived from OVA-immune donor mice and cultured 5 days with irradiated E.G7-OVA cells before transfer. RESULTS: E.G7-OVA tumor-bearing mice given TBI and OVA-immune bone marrow showed a significantly increased cure rate when compared with that among controls reconstituted with nonimmune bone marrow after TBI (logrank, P < .01). The antitumor effect of immune bone marrow was abrogated by T-cell depletion of the marrow graft (P < .016). The antitumor effect of immune marrow was enhanced by the addition of OVA immunization of tumor-bearing recipients (P < .015). OVA-specific cytotoxic T-lymphocyte (CTL) activity was recovered from tumor-bearing recipients of immune marrow 14 days after bone marrow transplantation. The antitumor effect observed following the adoptive transfer of immune marrow was further augmented by the addition of 1 x 10(7) splenic E.G7-OVA-specific in vitro activated CTLs derived from OVA-immune mice (P < .03). CONCLUSION: These studies establish the principle that antigen-specific T-cell immunity against a defined tumor-specific antigen can be transferred with bone marrow from an immune donor. IMPLICATIONS: Active immunization of normal human bone marrow or T-cell donors with a refined, safe tumor antigen and transfer of immunity to the patient may represent a novel strategy for circumventing the obstacle of host immune suppression associated with the tumor-bearing state.

Animals↗
PubMed2004

Coming out of the closet: opening agencies to gay and lesbian adoptive parents.

Gay men and lesbians often encounter barriers when they pursue adoption. Adoption workers are expected to make decisions regarding child placement using the best interest standard. However, this decision-making model does not adequately consider intrapersonal, interpersonal, and organizational factors that affect the use of the standard. This article examines the best interest standard and makes practice recommendations to increase the accessibility of adoptions for gay and lesbian applicants.

Adoption↗
PubMed2004

Emerging infectious disease issues in international adoptions: severe acute respiratory syndrome (SARS), avian influenza and measles.

PURPOSE OF REVIEW: New emerging infections over the last few years demonstrate the potential for the introduction of epidemic illness through global migration. The increasing number of children adopted internationally (>20,000 in 2003, from the United States State Department) provides a unique situation for the spread of emerging infections through the combination of international travel by parents through areas where such infections may be contracted and the nature of the living conditions for many of the orphans being placed by this process. RECENT FINDINGS: The recent literature on three emerging infections--avian influenza, severe acute respiratory syndrome (SARS) and measles--describes clinical aspects of the illnesses and their epidemiology. For avian influenza aspects of the agrarian economy in southeast Asia enabled the virus to reach the human population. The potential for further adaptation to people could set the stage for a new pandemic. SARS evolved in rural China and spread worldwide in one season with an approximate 10% mortality. Attention to public-health measures led to control of this new illness. Most recently, outbreaks of measles in Chinese orphanages have been documented. These findings demonstrate the potential of such infections to be transmitted during the process of international adoption, and in the case of measles the realization of this potential in recent reported cases from Chinese orphanages brought to the United States on commercial airlines. SUMMARY: Clinicians involved in international adoption and public-health officials assessing emerging infections need to work together in monitoring these issues.

Adolescent↗
PubMed1991

In vivo proliferation of adoptively transferred tumor-infiltrating lymphocytes in mice.

The adoptive transfer of tumor-infiltrating lymphocytes (TILs) in conjunction with interleukin-2 (IL-2) administration can mediate a reduction in established pulmonary and hepatic metastases of a variety of murine tumors as well as in patients with metastatic melanoma. To characterize further the fate of adoptively transferred TILs, the uptake of the thymidine analog 5-[125I]iodo-2-deoxyuridine ([125I]UdR) into the DNA of dividing cells was used to study the in vivo proliferation and migration patterns of transferred TILs in C57BL/6N mice. Animals received 500 rad of total body irradiation prior to cell transfer to separate incorporation of radiolabel into endogenous lymphoid cells from that into transferred TILs. Mice were subsequently treated with i.v. injections of TILs or no cells followed by i.p. injections of Hanks' balanced salt solution or IL-2. At various time points, mice received [125I]UdR, and 20 h later tissues were removed and counted on a gamma analyzer. A proliferation index (PI) was calculated by dividing the mean cpm of organs of experimentally treated mice by the mean cpm of organs of control mice. Animals receiving TILs alone demonstrated small increases in [125I]UdR in the lungs, liver, and spleen of saline-treated controls (PI = 1.4, 1.6, and 1.7, respectively, on day 4), while animals treated with 50,000 U of IL-2 alone showed greater increases in the lungs, liver, kidneys, and spleen (PI = 3.9, 6.1, 3.3, and 15.8). Mice receiving TILs plus IL-2 demonstrated the highest levels of radiolabel incorporation in the same organs (PI = 10.5, 19.4, 10.2, and 22.4). Over a period of 10 days, TIL plus IL-2 treated animals continued to incorporate significantly greater amounts of [125I]UdR for as long as high-dose IL-2 was administered. Animals treated with TILs demonstrated increased incorporation of radiolabel with increasing doses of IL-2. Injection of irradiated TILs did not result in an increased uptake of [125I]UdR into these tissues, thus confirming that TIL proliferation is responsible for the radiolabel uptake in animals receiving TILs alone or TILs plus IL-2. Additionally, fluorescein-labeled anti-Thy-1.1 antibody identified proliferating TILs derived from congenic B6.PL Thy 1a/CY (Thy-1.1) animals in the lungs, spleen, and liver of recipient C57BL/6N (Thy 1.2) mice. In summary, we have demonstrated that adoptively transferred TILs distribute widely after i.v. injection and can proliferate in various tissues especially under the influence of exogenous IL-2.

Animals↗
PubMed1993

Reversal of feline leukemia virus infection by adoptive transfer of lectin/interleukin-2-activated lymphocytes, interferon-alpha, and zidovudine.

Previous experimental studies utilizing human recombinant interferon-alpha-2b (IFN alpha-2b) alone or with zidovudine (AZT) to treat established feline leukemia virus (FeLV) infection resulted in a significant reduction in circulating virus throughout a 49-day treatment period. However, the anti-FeLV effect of IFN alpha was limited by the production of IFN alpha-neutralizing antibodies detected 7 weeks after the start of treatment. AZT without IFN alpha had no effect on circulating virus load. To examine the hypothesis that combination chemoimmunotherapy might induce the clearance of FeLV infection, persistently infected cats were infused with activated lymphocytes, IFN alpha, and AZT 12 weeks after infection with FeLV. Recipient cats received weekly infusions of 1.46 x 10(8) lymphocytes activated in vitro with lectin/IL-2 comprised of 98% T cells and an even distribution of CD4+ and CD8+ lymphocytes. FeLV infection was cleared in 4 of 9 cats receiving combined therapy after four adoptive cell transfers. These cats remained negative for circulating virus during a 63-day treatment period (17 adoptive cell transfers) despite the production of anti-IFN alpha-neutralizing antibodies. Sequential development of virus-neutralizing and virus envelope antibody titers were detected in those cats which cleared retroviremia, an antiviral response that was absent in untreated control animals or nonresponders. Three of four responder cats remained negative for FeLV 95 days after treatment was discontinued. Treatment of cats with lymphocytes without chemotherapy failed to influence the course of FeLV infection. These results suggest that combined treatment using IFN alpha and adoptive lymphocyte transfer served to reconstitute antiviral humoral immunity, counteract immunosuppression, and induce the reversal of retroviremia.

Animals↗
PubMed1994

Effect of interleukin-1 alpha on the in vitro activation of tumor-draining lymph node cells for adoptive immunotherapy.

Adoptive immunotherapy using in vitro activated T-cells can mediate the destruction of metastatic tumor deposits in animal models. These antitumor effector cells can be generated from mice with subcutaneous tumor by the sequential in vitro activation of tumor-draining lymph node (TDLN) cells with monoclonal antibody to the T-cell receptor complex (anti-CD3) and expansion in low concentrations of interleukin-2 (IL-2). In this animal model, the concomitant presence of visceral tumor can suppress the sensitization of tumor-reactive TDLN cells. We investigated whether IL-1 alpha added during in vitro activation and/or expansion of TDLNs could augment their antitumor activity in adoptive therapy. Mice were inoculated subcutaneously with MCA 205 tumor. TDLN cells were harvested and activated in vitro with 1 microgram/ml anti-CD3 for 2 days (anti-CD3 phase), followed by expansion in 10 U/ml IL-2 for 3 days (IL-2 phase). Experimental cultures had IL-1 (10-10,000 U/ml) added in either or both phases. After the 5-day culture period, cells were counted to determine in vitro cellular proliferation and then adoptively transferred to mice bearing 3-day established lung metastases to assess in vivo antitumor efficacy. IL-1 added during the anti-CD3 or IL-2 phase did not alter in vitro cellular proliferation. The presence of IL-1 during the anti-CD3 phase led to the generation of cells that were significantly more therapeutically efficacious than cells generated in the absence of IL-1. The effect of IL-1 during anti-CD3 activation appeared to be dose dependent in the concentration range 10-1,000 U/ml. The addition of IL-1 during the IL-2 phase only did not enhance the antitumor reactivity of the activated cells. The beneficial effect of IL-1 during the anti-CD3 activation phase was specific for the tumor against which the TDLN had been initially sensitized; also, there was no evidence that non-tumor bearer lymphocytes developed significant antitumor reactivity when "activated" with IL-1 and anti-CD3. Furthermore, addition of IL-1 during the anti-CD3 activation phase abrogated suppression induced by the concomitant presence of lung metastases during subcutaneous tumor growth. IL-1 appears to up-regulate the in vitro activation of tumor-reactive lymphocytes derived from TDLN, in both the presence and the absence of visceral metastases.

Animals↗
PubMedDate not supplied

Adoptive transfer from interferon-alpha-fed mice is associated with inhibition of active experimental autoimmune encephalomyelitis by decreasing recipient tumor necrosis factor-alpha secretion.

Ingested type I interferon (IFN) suppresses clinical relapse in murine chronic experimental autoimmune encephalomyelitis (EAE), inhibits clinical attacks more effectively than subcutaneous doses, and decreases the adoptive transfer of EAE. To determine whether splenocytes from IFN-fed donors were "suppressor-like" populations, donor SJL/J mice were immunized and fed with mock IFN-alpha or with IFN-alpha every other day for at least 4 weeks after initial clinical attack. Recipients of adoptively transferred CD8+ T cells from mock IFN-alpha-fed donors showed no clinical improvement of clinical disease compared with actively immunized controls. In contrast, recipients of adoptively transferred CD8+ T cells from IFN-alpha-fed donors showed decreased clinical disease compared with recipients of mock IFN-alpha-fed CD8+ T cells. To evaluate the mechanism of protection by donor CD8+ T cells and to determine if ingested IFN-alpha activates natural immunomodulatory cell populations, the authors used the acute EAE model and naïve-fed donor animals as sources of T cells and CD8+ T cells. Con A-activated spleen T cells from naïve nonimmunized mock IFN-alpha-fed donors inhibited actively induced disease and showed decreased recipient TNF-alpha secretion compared with recipients of T cells from mock IFN-fed mice. Donor activated spleen CD8+ T cells from naïve nonimmunized IFN-alpha-fed animals suppressed actively induced EAE in recipients and showed decreased IFN-gamma and TNF-alpha proinflammatory secretion. Decreased recipient TNF-alpha secretion correlates best with the disease protection from IFN-fed T and CD8+ T cells.

Administration, Oral↗
PubMedDate not supplied

Persistence of multiple tumor-specific T-cell clones is associated with complete tumor regression in a melanoma patient receiving adoptive cell transfer therapy.

The authors recently reported that adoptive immunotherapy with autologous tumor-reactive tumor infiltrating lymphocytes (TILs) immediately following a conditioning nonmyeloablative chemotherapy regimen resulted in an enhanced clinical response rate in patients with metastatic melanoma. These observations led to the current studies, which are focused on a detailed analysis of the T-cell antigen reactivity as well as the in vivo persistence of T cells in melanoma patient 2098, who experienced a complete regression of all metastatic lesions in lungs and soft tissues following therapy. Screening of an autologous tumor cell cDNA library using transferred TILs resulted in the identification of novel mutated growth arrest-specific gene 7 (GAS7) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene transcripts. Direct sequence analysis of the expressed T-cell receptor beta chain variable regions showed that the transferred TILs contained multiple T-cell clonotypes, at least six of which persisted in peripheral blood for a month or more following transfer. The persistent T cells recognized both the mutated GAS7 and GAPDH. These persistent tumor-reactive T-cell clones were detected in tumor cell samples obtained from the patient following adoptive cell transfer and appeared to be represented at higher levels in the tumor sample obtained 1 month following transfer than in the peripheral blood obtained at the same time. Overall, these results indicate that multiple tumor-reactive T cells can persist in the peripheral blood and at the tumor site for prolonged times following adoptive transfer and thus may be responsible for the complete tumor regression in this patient.

Amino Acid Sequence↗
PubMed1992

Can oncogene (RAS) activation predict susceptibility of human melanoma to activated lymphocytes and, therefore, the clinical response of such neoplasms to adoptive immunotherapy?

The expression of activated ras oncogenes was found to be associated with that of tumour-specific transplantation antigens in mouse tumours, which can be cured by adoptive immunotherapy with T lymphocytes and interleukin-2 (IL-2). A similar association is here proposed to exist between RAS oncogene activation (mutation) in human melanoma and susceptibility of these tumours to the lytic action of activated lymphocytes (both lymphokine-activated killers and cytotoxic T cells) which have been used, along with IL-2, in the adoptive immunotherapy of advanced melanomas. The limited clinical response (15-25%) of melanoma patients to different immunological therapies is, therefore, considered to be due to a similar frequency of immunogenic, RAS+ melanomas. The authors thus suggest that RAS activation might be a marker of immunogenicity and that only the subset of melanoma cells expressing activated RAS will in turn possess tumour antigens which can be the target of immunotherapeutic, activated lymphocytes. It is then predicted that RAS+ melanomas will be more susceptible to adoptive immunotherapy than RAS-counterparts.

Animals↗
PubMed2006

The adoption of children from public care: a prospective study of outcome in adolescence.

OBJECTIVE: To discover the outcomes for children placed late for adoption (between 5 and 11 years old) from public care and to establish which factors predict poorer outcome. METHOD: Data were collected prospectively (1993-2003) from a representative sample of domestic U.K. adoptive placements (N = 108) at the start of placement, at 1 year, and 6 years later. Most of the children entered care because of abuse and neglect. Outcome was assessed by the disruption rate, by a twofold classification of the character of continuing placements, and by an assessment of psychological well-being. RESULTS: At the adolescent follow-up, 23% of placements had disrupted, 49% were continuing positively, and 28% were continuing but with substantial ongoing difficulties. Four factors contributed independently to a higher risk of disruption: older age at placement (odds ratio = 1.07), having been singled out from siblings and rejected (5.87), time in care (1.04), and a high level of behavioral problems (1.25). Two factors predicted differences in continuing placements. CONCLUSIONS: Late adoption can be successful in that half the children made good progress, but the extent of disruptions and difficulties in continuing placements gives rise to concern. Knowledge of predictors will help in devising planning pre- and postplacement support services.

Adolescent↗
PubMed2002

Parent-offspring resemblance for reading performance at 7, 12 and 16 years of age in the Colorado Adoption Project.

BACKGROUND: The study aimed to conduct the first analysis of CAP parent-offspring resemblance for reading performance in children aged 7, 12 and 16 years, and to assess the etiology of individual differences in reading performance of children at 16 years of age. METHOD: The Reading Recognition subtest of the Peabody Individual Achievement Test was administered to children in the Colorado Adoption Project (CAP) at 7, 12 and 16 years of age, and to their adoptive and nonadoptive parents when the children were 7 years of age. RESULTS: Resulting parent-offspring correlations in adoptive families were not significant at any age, but correlations between scores of nonadoptive control parents and their offspring were significant at all three ages. CONCLUSIONS: Results obtained from behavioral genetic model-fitting analyses of data from parents and their children tested at age 16 are consistent with results of studies of twins and siblings indicating that individual differences in reading performance are due substantially to genetic influences. In contrast, environmental transmission from parents to offspring was negligible, suggesting that environmental influences on individual differences in the reading performance of children are largely independent of parental reading performance.

Adolescent↗
PubMed2004

A mouse model of pemphigus vulgaris by adoptive transfer of naive splenocytes from desmoglein 3 knockout mice.

BACKGROUND: Pemphigus vulgaris (PV) is an autoimmune blistering disease caused by antidesmoglein3 (anti-Dsg3) IgG autoantibodies. Recently, we developed a PV mouse model by adoptive transfer of splenocytes from recombinant Dsg3-immunized Dsg3(-/-) mice to Rag2(-/-) immunodeficient mice that expressed Dsg3. OBJECTIVES: We determined whether the adoptive transfer of naive splenocytes from nonimmunized Dsg3(-/-) mice induces the anti-Dsg3 IgG production and the PV phenoytpe in recipient mice. METHODS: We adoptively transferred naive Dsg3(-/-) splenocytes into Rag2(-/-) mice and compared their PV phenoytpe with those mice receiving immunized Dsg3(-/-) splenocytes. The numbers of splenocytes and their subpopulations required for anti-Dsg3 IgG production were examined. RESULTS: Mice that received naive Dsg3(-/-) splenocytes produced anti-Dsg3 IgG, which bound to keratinocyte cell surfaces in vivo, and developed the PV phenotype, including oral erosions with suprabasilar acantholysis. Antibody production and the appearance of the PV phenotype were delayed by approximately 2 weeks in mice that received naive splenocytes compared with mice that received immunized splenocytes. However, once the PV phenotypes developed, there were no apparent differences in disease severity between the two models. Interestingly, the anti-Dsg3 IgG titres were significantly lower in mice that received naive splenocytes than in mice that received immunized splenocytes, suggesting that the former antibodies were more potent than the latter. The frequency of anti-Dsg3 IgG production depended on the number of transferred naive splenocytes. Both CD4+ T cells and B220+ B cells from naive Dsg3(-/-) mice were essential for the production of anti-Dsg3 IgG antibodies. CONCLUSIONS: Dsg3-specific naive lymphocytes in Dsg3(-/-) mice can be primed and activated by the endogenous Dsg3 in recipient mice to produce pathogenic anti-Dsg3 IgG without active immunization. This approach using naive lymphocytes provides a unique model to dissect immunological mechanisms of tolerance against peripheral autoimmune targets.

Adoptive Transfer↗
PubMed1991

Intercountry adoption: a review of the evidence.

Studies of the outcome of intercountry adoption are reviewed in the context of its history and politics. Intercountry adoption is a post-World War II phenomenon, and has become largely a service for childless couples in the West. Many Third World countries, and some Western social workers, are bitterly opposed to the practice, on both political and psychological grounds. Outcome studies have produced results similar to those found in studies of incountry adoption, although, to date, insufficient attention has been paid to issues of identity and racism. The policy implications of these studies will depend on political considerations, as well as the research evidence.

Acculturation↗
PubMed1994

Infant relinquishment through adoption.

The confidential nature of adoption and the stigma associated with out-of-wedlock pregnancies have limited the number of studies of infant relinquishment. Birthmothers' feelings of loss and grief have not been widely acknowledged. The purpose of this study was to describe the experiences of 12 women who had relinquished their infants for adoption. Data were collected using open-ended questions to describe the experiences. Type of adoption influenced the experience of infant relinquishment. Four themes represented the process of relinquishment.

Adaptation, Psychological↗
PubMedDate not supplied

Helping infertile couples explore the option of adoption.

Adoption often is considered an ideal option for infertile couples. This article presents topics health-care professionals should address when discussing adoption with infertile couples and delineates interventions for anticipatory guidance once they decide to adopt.

Adaptation, Psychological↗