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PubMed2006

Adoptive T-cell therapy of cancer.

Adoptive therapy involves the transfer of ex vivo expanded immune effector cells to patients as a means of augmenting the antitumor immune response. In general, this transfer is accomplished by harvesting cells from the peripheral blood, tumor sites, or draining lymph nodes and expanding effector cells in a specific or nonspecific fashion for adoptive transfer. This article describes the rationale for adoptive T-cell therapy, the developments that have led to the translational application of this strategy for the treatment of cancer, the challenges that have been addressed, and future approaches to the development of adoptive therapy as a treatment modality.

Antigens, Neoplasm↗
PubMed2003

New tools for quantifying and visualizing adoptively transferred cells in recipient mice.

Adoptive transfer of donor cells in mice is widely used in research on the function and metabolism of lymphocytes. We have evaluated new approaches for quantifying and visualizing adopted cells in recipient mouse tissue. We injected spleen cells from male beta-galactosidase (LacZ) transgenic mice into female wild type mice and assessed the robustness of real-time PCR for quantifying the accumulation of the donor cells in blood and tissues of the recipient mice. The clearance of donor cells from the blood and their recruitment in lung, spleen, liver, and kidney was almost identical when obtained with amplification of the donor cell-specific LacZ or sex-determining region on the Y-chromosome (SRY) gene. We found, however, a marked difference in the PCR amplification efficiency of genomic DNA of different tissues, which should be taken into account when comparing recruitment of donor cells in different tissues. To visualize adoptively transferred cells, we used either spleen cells from transgenic mice, which express a Green Fluorescent Protein (GFP) transgene or spleen cells that had been fluorescence labeled ex vivo with CellTracker Orange. Whereas ex vivo and in vivo labeled donor cells could easily be detected in recipient mouse tissue by laser scanning confocal microscopy, only CellTracker Orange-labeled cells could be detected by conventional fluorescence microscopy due to autofluorescence in the examined tissues. Importantly, CellTracker Orange labeling did not appear to affect the blood clearance or the tissue accumulation of the donor cells. Together, the results demonstrate the usefulness of new protocols for quantifying and visualizing adoptively transferred cells by genetic tracing or fluorescence labeling.

Adoptive Transfer↗
PubMed2005

International adoption: what is fact, what is fiction, and what is the future?

Despite the popularity of international adoption in North America and Western Europe as a means to build a family, the knowledge of health care professionals is often limited regarding the historical context of this phenomenon as well as the motivations and process experienced by adoptive parents. Although international adoption is viewed as an acceptable if not admirable method of forming kinships in accepting countries, opinions in the international community are mixed. Whether international adoptions increase or are drastically curtailed depends on addressing the misgivings that many countries have about placing their children abroad. Concerns center in two broad areas: sensitivity toward preservation of family and culture and whether the process has sufficient integrity to act in the best interests of children and birth parents.

Adoption↗
PubMed2005

Immediate behavioral and developmental considerations for internationally adopted children transitioning to families.

The arrival of a newly adopted child into the family is usually a joyous time. Behavioral concerns arise in many internationally adopted children, most of whom are infants or toddlers at the time of placement with their adoptive families. Problems with feeding, sleeping, and other daily activities are often prominent in the first few weeks after the adoption. Some children display emotional distress and developmental delays; however, most recover rapidly. Anticipatory guidance from the pediatrician can assist families and children with this major life transition.

Adoption↗
PubMed1997

Manipulation of Th1/Th2 balance in vivo by adoptive transfer of antigen-specific Th1 or Th2 cells.

We have investigated the possibility that the Th1/Th2 balance in vivo may be modulated by adoptive transfer of Th1 or Th2 cells induced in vitro. Thl cells were induced from I-Ad-binding OVA323-339-specific T-cell receptor-transgenic (TCR-Tg) mouse spleen cells by culturing with OVA323-339 peptide and antigen presenting cells (APC) in the presence of IL-2, IL-12 and anti-IL-4 mAb. Th2 cells were induced from TCR-Tg mouse spleen cells by culturing with IL-2, IL-4 and anti-IL-12 mAb in addition to OVA323-339 plus APC. Immunomodulating activities of both Th1 and Th2 cells were determined by their effect on delayed type hypersensitivity (DTH) responses or cytokine production. No significant DTH responses (footpad swelling) were observed in untreated BALB/c mice following a single injection of OVA323-339-pulsed syngeneic spleen cells. However, adoptive transfer of Th1 cells into BALB/c mice induced strong dose dependent DTH responses in response to I-Ad-bound OVA323-339 but not unrelated peptide. In contrast, only slight DTH responses were detected in BALB/c mice transferred with Th2 cells. In parallel with the DTH responses, increased levels of serum IFN-gamma were demonstrated in mice adoptively transferred with Th1, while no significant increase was observed in Th2-transferred mice. In vitro analysis also demonstrated that both spleen cells and popliteal lymph node cells prepared from Th1-transferred mice showed Th1-type cytokine production, while cells obtained from Th2-transferred mice revealed Th2-dominant cytokine production. Such immune deviation induced by antigen-specific Th1 cells was demonstrated up to three months after cell transfer. Therefore, it may be possible to manipulate the Th1/Th2 balance in vivo by adoptive transfer of antigen-specific Th1 or Th2 cells.

Adoptive Transfer↗
PubMed1977

Familial resemblance of body weight and weight/height in 374 homes with adopted children.

Body weight and weight/height were measured in 535 children adopted at the median age of 3 months, and in 250 natural children in French-Canadian origin living in 374 Montreal homes, to determine whether the shared environment contributed to the familial resemblance of weight in children aged one to 21. The mid-parent vs natural children's correlation ( r2 X 100) was 9.55% for body weight and 6.60% for W/H (p less than 0.01), whereas the mid-parent vs adopted children's correlation was 0.00% for both characteristics. The sib-sib correlation in 80 homes with greater than 1 natural child was 15.2% for weight and 13.48% for W/H (p less than 0.001), whereas in 138 homes with greater than 1 adopted child, the adoptee-adoptee correlations were, respectively, 0.00% and 0.07%. It is concluded that heredity explains most of the familial aggregation of patterns of weight and weight/height in children. This conclusion does not necessarily apply to obesity, since weight indices in children do not accurately reflect excess fat tissue, and half of the adoptees were adopted after the age of three months.

Adoption↗
PubMed2002

Induction of maternal behavior in non-parturient adoptive mares.

An attempt was made to elicit maternal behavior in non-parturient Welsh pony mares through a combination of hormonal treatment and vaginal-cervical stimulation (VCS). Lactation was induced in 16 nonpregnant, non-parturient mares via a combination of estradiol, progesterone and a dopamine antagonist (sulpiride). During the adoption trials, each lactating mare was confined behind a padded bar and a newborn foal was held near her head. Eight of the mares received two 3-min periods of VCS when the foster foal was introduced. Following VCS, the foal was released and its interactions with the adoptive mare observed until the acceptance criterion was met (i.e. the mare accepted the foal at the udder with no signs of aggression). The remaining eight adoptive mares were treated in the same manner but did not receive VCS. All 16 non-parturient mares eventually accepted and nursed their adopted foal. However, acceptance latencies were significantly shorter for mares in the VCS condition than for those without VCS, and did not differ between the VCS condition and a group of control mares with their biological offspring. In subsequent choice tests, both groups of foster mares (with/without VCS), like the control mares, displayed a preference for their 'own' foal. Once the non-parturient mares accepted their foster foal, their maternal behavior resembled that of control mothers. The positive effect of VCS on maternal acceptance may reflect a release of oxytocin triggered by this treatment.

Administration, Topical↗
PubMed2001

The path to adoption for children of color.

OBJECTIVE: This article focuses on the path to adoption for children involved in the public child welfare system. METHOD: Descriptive and event history analyses were conducted of 1,550 children who had been removed from their homes and placed in out of home care in the child welfare system in Kansas and have adoption as a goal. RESULTS: African American children consistently took longer to reach significant milestones, including adoption placement and finalization. CONCLUSION: African American children are over-represented throughout the progression from substantiated abuse to adoption. Future research in other states should focus on whether this trend is unique to Kansas or applicable in other states. Additionally, efforts should be devoted to investigating the social, psychological, cultural, and systemic factors contributing to this differential treatment. Finally, there is a dire need to develop and evaluate interventions targeted at meeting the specialized needs of African American children in this system.

Adoption↗
PubMed2003

Transforming growth factor-beta induces apoptosis in antigen-specific CD4+ T cells prepared for adoptive immunotherapy.

Transforming growth factor-beta (TGF-beta), found at the site of most tumors, has been recognized as one of the mechanisms involved in tumor immunological escape. To evaluate its impact on adoptive immunotherapy against cancer, we examined the susceptibility of tumor-specific T cells to TGF-beta in the setting of these T cells being prepared for adoptive transfer. Hepatitis B virus (HBV)-specific CD4(+) T cells were ex vivo generated by activating with HBV-transfected dendritic cells and selecting with antibodies to CD25 activation molecules, and then expanded with antibodies to CD3/CD28. These T cells expressed higher levels of the type II TGF-beta receptor than nai;ve T cells and exhibited enhanced apoptosis when exposed to TGF-beta. The underlying apoptotic pathway was linked to the dissipation of the mitochondrial inner membrane potential and activation of caspase-9. The absence of caspase-8 activity in TGF-beta-treated T cells suggests that the death receptor system may not be involved in this type of apoptosis. Interleukin-2 (IL-2), which is concomitantly administered with tumor-specific T cells in adoptive immunotherapy, was unable to protect HBV-specific CD4(+) T cells from the pro-apoptotic effect of TGF-beta when added simultaneously with TGF-beta. Interesting, IL-2-pretreated T cells displayed the type II TGF-beta receptor at lower levels and were more resistant to TGF-beta. Together, our findings indicate that the effectiveness of adoptive cancer immunotherapy may be impaired by tumor-derived TGF-beta and appropriate manipulation of exogenous IL-2 might overcome this hurdle.

Animals↗
PubMed1997

The impact of psychological stress on the efficacy of anti-viral adoptive immunotherapy in an immunocompromised host.

Adoptive immunotherapy represents a potentially effective approach by which to control the extent of viral infections in an immunocompromised host. However, the impact of psychological stress and its associated neuroendocrine components on the efficacy of such a treatment strategy has yet to be determined. In the studies described herein, we have developed and utilized a model of primary, local herpes simplex virus (HSV) infection in radiation-induced, immunosuppressed C57BL/6 mice to investigate the role of stress in altering the protective capacity of adoptively transferred lymphocytes that contribute to the resolution of primary HSV infection. The sublethal dose of irradiation chosen for this model was shown to abrogate the local, adaptive immune response to HSV infection as measured by the degree of in vivo lymphoproliferation, development of HSV-specific cytotoxic T lymphocytes (CTL), and production of gamma interferon (IFN-gamma). Both short- and long-term acute stress, applied in the form of physical restraint, diminished the effectiveness of adoptively transferred lymphocytes as was indicated by an enhancement of viral replication in the footpad tissue and an increased rate of mortality. A reduction in the levels of IFN-gamma at the site of primary HSV infection represented at least one mechanism underlying this suppression of anti-viral immunity. Furthermore, the time-dependent restoration of immune function following irradiation was shown to be compromised in mice subjected to the restraint stress procedure. Together, these findings emphasize the potential role of psychological stress in suppressing both the capability of adoptive immunotherapeutic procedures to combat viral infection and the reestablishment of immune function in individuals who have undergone immunosuppressive therapy.

Adoptive Transfer↗
PubMed1998

Is adoption a risk factor for the development of adjustment problems?

The extent to which being adopted increases a child's risk for the development of adjustment problems has been debated for decades. Results from studies examining prevalence of adopted children and adolescents in outpatient and inpatient mental health treatment suggest that the risk associated with adoption is modest or nonexistent. This body of research is reviewed and critiqued. Two possible explanations for the apparent disparate findings of the clinically based and nonclinically based studies are explored: biases in referral for mental health treatment and the influence of the shape of the distribution of adjustment problems in the adopted and nonadopted populations. Implications for clinical practice and future research are explored.

Adaptation, Psychological↗
PubMed2002

Adoption and the effect on children's development.

Adoption, whether formal or informal, has always been a superior method of assuring survival for children whose parents are unwilling or unable to care for them. However, adoption can also affect child development in profound ways. Data collected over the past three decades support adoption as a superior means of promoting normal development in children permanently separated from birth parents. Out of calamity and loss, children recover and progress to become functionally and emotionally competent adults. For children suffering severe neglect or abuse in early life, an adoptive family is a remarkable environment for healing emotional and physical trauma and reversing developmental deficits.

Adoption↗
PubMed1998

[Adoption and chronic hepatitis B carrier state].

AIM: Because there are few adoptable children in France, parents, for the last 20 years, have turned to international adoption. Alerted by the generally poor health of these children, we paid particular attention to their health problems and especially to infection by hepatitis B virus (HBV). POPULATION AND METHODS: The 60 internationally-adopted children seen from June 1993 to June 1997 were included in this study. All had hemogram and serum iron dosage, and search for intestinal parasites and tuberculosis was performed in each child, as were HBs antigen and HBs antibody screening. When HBs antigen was positive, HBe antigen and antibodies, HBV DNA and hepatitis C and delta serology were also studied. RESULTS: Six out of the 60 children were HBV chronic carriers. The six presented HBs antigen and five out of the six presented viral DNA. One child was co-infected with delta virus. Serum aminotransferase was normal in three children and increased in the three others. DISCUSSION: Some internationally adopted children are exposed to chronic infection by HBV. This concerns children coming from countries known for the high frequency of the disease, but also children with long stay in Eastern European nurseries. Chronic HBV carriage puts the child, as well as the family and other children in institutions and/or schools at risk, thus necessitating preventive measures.

Adoption↗
PubMed2002

Distribution of adoptively transferred, tumor-sensitized lymphocytes in the glioma-bearing rat.

For adoptively transferred lymphocytes to exert anti-tumor effects in vivo, they must traffic or initiate the migration of endogenous immune cells to the site of tumor. Using a rat model, we examined the trafficking of tumor-sensitized lymphocytes to an intracerebral glioma. By labeling the cells with 111Indium oxine (111In) prior to intravenous injection, we were able to quantify the relative number of lymphocytes that traveled to the tumor site. There was no difference in lymphocytic influx between the tumor-bearing and non-tumor-bearing cerebral hemispheres in 3-day rat glioma models. However, in 7-day models, significantly greater numbers of 111In-labeled lymphocytes resided in the tumor-bearing hemisphere at 12 h post-administration. This number increased more than two-fold by 24 h post-adoptive transfer. Using fluorescent-labeled lymphocytes and microscopy, we confirmed that the detection of radioactivity within the brain was truly due to tumor infiltrating 111In-labeled lymphocytes. Adoptively transferred cells were found in perivascular and peritumoral locations. These data demonstrate that tumor-sensitized lymphocytes traffic to an intracerebral target site where they can exert an effect, further supporting adoptive immunotherapy as a treatment for glioma.

Adoptive Transfer↗
PubMed2004

Regression of bone metastases following adoptive transfer of anti-CD3-activated and IL-2-expanded tumor vaccine draining lymph node cells.

As many as 80% of patients with breast, prostate, or lung cancer develop bone metastases during the course of their illness. However, thus far, no attempts have been made to explore the potential value of adoptive immunotherapy with antigen-specific T lymphocytes specifically for the treatment of skeletal metastases. Here, we demonstrate tumor regression in a preclinical model of bone metastases from the murine B16BL6 melanoma following adoptive transfer of effector T lymphocytes obtained from tumor vaccine draining lymph nodes. The antitumor effect required transfer of high number of effector cells, which was dependent on CD8+ cells as demonstrated by in vivo depletion of different T cell subsets, and was magnified if effector cells were administered to the arterial supply of the bone/bone marrow. Using flow cytometric analysis, CFSE-labelled Thy1.1+ donor T cells were isolated from the bone marrow of tumor-bearing mice at 24 h and 6 days following adoptive transfer. At the latter time point cell division of the transferred effector cells was detectable. Currently, no curative treatment is known for skeletal metastases in clinical practice. Considering the promising early findings in the present study, further studies exploring the therapeutic potential of adoptive immunotherapy for metastatic disease to the skeleton are warranted.

Animals↗
PubMed2001

Role of NK cells in adoptive immunotherapy of metastatic colorectal cancer in a syngeneic rat model.

This article reviews our immunotherapy research with natural killer (NK) cells in a syngeneic rat colorectal cancer liver and lung metastasis model. Using adoptive transfer of interleukin (IL)-2-activated NK cells, NK cells were shown to selectively infiltrate the tumors. More NK cells were found in tumors when the NK cells were directly injected into tumor-draining blood vessels than when the cells were injected in systemic blood vessels. Under optimal conditions, a limited, though significant, effect of adoptively transferred NK cells on tumor growth was shown. We observed that both endogenous and adoptively transferred NK cells were predominantly present in the stroma surrounding the tumor cell nodules. It is possible that they did not penetrate the nodules containing the tumor cells because of the presence of a basal membrane-like structure around these nodules. Adoptively transferred NK cells may initiate elimination of tumor cells by activating other effector cells, whereas some may eliminate tumor cells by direct cell-cell contact. A diverse array of molecules was shown to be involved in this process. CD45 on NK cells was found to be important in initiating the lysis-inhibitory signal upon binding of 'self' major histocompatibility complex (MHC) class I on potential target cells. Our results indicate that NK-cell cancer therapy is still promising and needs improvement.

Animals↗
PubMed1977

Patterns of interest similarity in adoptive and biological families.

Twin studies have indicated that genetic differences among individuals also contribute to interest and personality differences among them. In this study, 114 biologically related families and 100 adoptive families were administered the Strong-Campbell Interest Inventory. The protocols of parents and their adolescent children (total N = 870) were scored on the six scales of Holland's model of interest styles (Realistic, Investigative, Artistic, Social, Enterprising, Conventional). Biological parent--child correlations ranged from -.13 to +.40, with 15 of the 24 scale correlations achieving significance; only 2 of the adoptive parent--child correlations were significant (range from -.15 to +.25). Biologically related pairs were also significantly more correlated than adoptive pairs for interest profiles. Same-sex biological siblings were more similar to each other than either opposite-sex siblings pairs or parent--child pairs. Pairs of unrelated children in the adoptive families were not too similar either on Holland's scales or the profile analysis.

Adolescent↗
PubMed1982

Personality resemblances between unwed mothers and their adopted-away offspring.

In a sample of 300 adoptive families there was a tendency for adopted children to be more extraverted and emotionally stable than biological children. For extraversion there was a low statistically significant resemblance between unwed mothers and their adopted-away children. Paradoxically, however, children of mothers with elevated Minnesota Multiphasic Personality Inventory (MMPI) scores tended to be rated as more emotionally stable than children of mothers with better adjustment on the MMPI. This latter finding was interpreted as suggested an interaction between emotional sensitivity and the early environment. According to this hypothesis, individuals with genotypes making them vulnerable to their environments could thrive in the warm climate of the adoptive families, but turn out relatively badly in the presumably less benign families in which the unwed mothers were reared.

Adoption↗