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Allogeneic bone marrow transplantation from a donor with severe active rheumatoid arthritis not resulting in adoptive transfer of disease to recipient.

We report a patient who underwent allogeneic bone marrow transplantation from a sibling with longstanding untreated severe active rheumatoid arthritis. After 4 years of follow-up there is no evidence of adoptive transfer of rheumatoid arthritis to the recipient. This case, along with another recently reported case, provides reassurance that haemopoietic stem cell transplantation from a donor with systemic autoimmune disease may not necessarily result in adoptive transfer of the disease. All previous reports of transfer of autoimmunity in humans have been of organ-specific autoimmune diseases and we speculate that pathophysiological differences might account for why systemic autoimmune disease is not transferred.

Adoptive Transfer↗

Adoptive autoimmune hyperthyroidism following allogeneic stem cell transplantation from an HLA-identical sibling with Graves' disease.

Autoimmune diseases which follow allogeneic BMT from a donor who is a patient or a carrier of an autoimmune condition are considered to be a paradigm of adoptive autoimmunity. Seven cases of autoimmune thyroiditis associated with clinical hyperthyroidism have been published to date. In the case reported here a 35-year-old female patient with AML of the M2 subtype received unmanipulated PBSC from her HLA-identical sister who had therapeutically controlled Graves' disease. Antithyroid antibodies, including thyrotropin receptor (TSHR) antibodies, appeared 1 year after transplant. Clinical hyperthyroidism requiring thyrostatic medication appeared after 2 years. The biological and clinical implications of adoptive, post-transplant autoimmunity are briefly discussed.

Adoptive Transfer↗

Adoptive transfer of small numbers of DX5+ cells alleviates graft-versus-host disease in a murine model of semiallogeneic bone marrow transplantation: a potential role for NKT lymphocytes.

Natural killer T (NKT) lymphocyte cells are a subset of regulatory lymphocytes with important immunemodulatory effects. Our aim was to evaluate the effect of transplantation of NKT lymphocytes on graft versus host disease (GVHD) in a murine model of semiallogeneic BMT. GVHD was generated by infusion of 2 x 107 splenocytes from C57BL/6 donor mice into irradiated (C57BL/6 x Balb/c)F1 recipient mice. Adoptive transfer of increasing numbers of DX5+ cells was performed. Recipient mice were followed for histological parameters of GVHD-associated liver, bowel, and cutaneous injury. Intrahepatic and intrasplenic lymphocytes were isolated and analyzed by FACS for CD4+ and CD8+ subpopulations. It was seen that adoptive transfer of 4.5 x 106 DX5+ cells significantly alleviated GVHD-related hepatic, bowel, and cutaneous injury, and improved survival (85% survival on day 28). In contrast, depletion of DX5+ cells led to severe GVHD-associated multiorgan injury and 100% mortality. A direct correlation with the number of transplanted DX5+ cells was noted (maximal effect with transplantation of 4.5 x 106 DX5+ cells). Tolerance induction was associated with an increased peripheral CD4/CD8 ratio, intrahepatic trapping of CD8 lymphocytes and a shift towards a Th2-type cytokine profile, manifested by decreased IL-12/IL10, IL-12/IL-4, IFNgamma/IL-10, and IFNgamma/IL-4 ratios. Transplantation of DX5+ cells holds promise as a novel therapeutic measure for GVHD.

Adoptive Transfer↗

Polyethylenimine-mediated transfection of human monocytes with the IFN-gamma gene: an approach for cancer adoptive immunotherapy.

Human monocytes (Mo) and monocyte-derived macrophages (MdM) are major effectors in host defense systems against cancer. Their antitumoral activity is dependent upon two processes: recruitment and activation. One of the most powerful activators for these cells is recombinant human IFN-gamma (rhIFN-gamma). However, when the potential of activated rhIFN-gamma was evaluated in clinical trials by ex vivo adoptive cellular immunotherapy protocols, the major problem was the short duration of ex vivo activation by rhIFN-gamma. Thus repeated injections were required to obtain a clinical response. To overcome this limitation we have developed a gene transfer protocol with IFN-gamma cDNA and polyethylenimine so as to obtain an efficient, long-lasting autocrine cytocidal activation in transfected human Mo/MdM. We show, by clonogenic assays, that efficient transfection and tumoricidal activity can be obtained by this method in human monocyte populations. Although the proposed model must be improved before clinical use, IFN-gamma producing monocytes have potential for adoptive immunotherapy.

Coculture Techniques↗

Adoptive immunotherapy for relapsed multiple myeloma after allogeneic bone marrow transplantation (BMT): evidence for a graft-versus-myeloma effect.

Adoptive immunotherapy with donor-derived buffy coat cells for relapsed hematological malignancies after allogeneic BMT is an established and highly effective treatment. We report a patient who relapsed on day +330 after allogeneic sibling BMT for multiple myeloma with multiple solid subcutaneous tumors consisting of plasma cells. Histology and immunocytology of the bone marrow did not show plasma cell infiltration. After cessation of the immunosuppression consisting of cyclosporine and methylprednisolone, a total of 6.2 x 10(7)/kg recipient body weight CD3+ T cells derived from the donor by leukapheresis were transfused on 4 consecutive days. To enhance the T cell effect six doses of 5 million units alpha interferon were given subcutaneously. Five days later the tumors started to shrink and have completely vanished since day x400 after BMT. The patient developed acute GVHD grade III of the liver and gut which was treated by reinduction of various immunosuppressive drugs. Up to now there is no evidence for relapse of the multiple myeloma, but the patient suffers from extensive chronic GVHD (gut and liver). This is the first report to demonstrate a graft-versus-myeloma effect for relapse with solid tumor manifestation after sibling BMT with donor-derived buffy coat cells as adoptive immunotherapy.

Antibodies, Monoclonal↗

Clinical course and immune response of a renal cell carcinoma patient to adoptive transfer of autologous cytotoxic T lymphocytes.

The cytotoxic T lymphocyte (CTL) is a promising candidate for an effector cell in adoptive immunotherapy for renal cell carcinoma (RCC). Here we report the clinical course and in vivo immune responses of a RCC patient with bulky retroperitoneal lymph node (RPLN) metastases who received adoptive autologous CTL therapy. A 56-year-old woman diagnosed with RCC with multiple RPLN metastases underwent unilateral nephrectomy. Autologous RCC cells were primary-cultured from surgical specimens. Before addition of peripheral blood mononuclear cells (PBMC) for CTL induction, subconfluent RCC cells were irradiated with 50 Gy. The PBMCs were then cultured on RCC cells in the induction medium supplemented with four kinds of interleukins. The induced CTLs showed the potent killing activity against autologous RCC cells in a typical MHC-class I-restricted manner. The patient received three courses of CTL therapy with a total of 10.2 x 10(9) cells, and the RPLN mass decreased markedly in size after the second course. Eosinophilia and enhanced CTL inducibility from peripheral blood were observed after CTL administrations. The patient was progression free without further treatment; however, she developed rapidly progressive glomerulonephritis more than 1 year after the last treatment. The patient died of newly developed metastases 27 months after the start of CTL therapy. At autopsy, viable RCC cells were found in multiple metastatic sites. However, only diffuse fibrous tissue was observed in the responding RPLN mass. Apparent histological divergence was observed between primary and metastatic sites.

Carcinoma, Renal Cell↗

Gonadotrophin releasing hormone agonist treatment with or without recombinant human GH in adopted children with early puberty.

BACKGROUND: Early onset of puberty is frequently observed in adopted children. During treatment with a gonadotrophin releasing hormone agonist (GnRHa), a decrease in height velocity (HV) precludes height gain. OBJECTIVE AND DESIGN: We studied the effect of the addition of GH to GnRHa treatment in a 3-year prospective randomized trial in 30 adopted children with early puberty. PATIENTS: Mean age (SD) at start of treatment was 9.6 (0.9) years in girls and predicted adult height (PAH) using a segmented bone age (BA) assessment method was 148.0 (5.3) cm. RESULTS: HV decreased gradually in both groups with a higher HV in the group with GH addition (group B). No significant difference between the rates of bone maturation [change in bone age (DeltaBA)/change in chronological age (DeltaCA)] of both treatment groups was observed. After 3 years of treatment, PAH increase was 5.7 (3.8) cm in group A (GnRHa alone) and 10.1 (3.8) cm in group B (P < 0.01). IGF-I levels were higher in group B. HV decreased slowly in both groups during treatment, unlike stabilization of IGF-I levels. CONCLUSION: We conclude that, after 3 years of treatment, the addition of GH to GnRHa results in higher HV and a significant increase in PAH compared to GnRHa alone.

Adoption↗

Adoptive transfer of donor-derived immunity by liver transplantation: a potential avenue to prevent hepatitis B virus reinfection.

Immunity to hepatitis B has been successfully transferred by bone marrow transplantation, but has also occurred after liver transplantation (LTx). This study was designed to analyse the influence of alloreactivity and immunosuppression, on the efficacy of adoptive immune transfer to hepatitis B by liver transplantation. Orthotopic LTx (n = 34) were performed in three rat strain combinations representing different genetic constellations. Donors had been vaccinated twice with recombinant hepatitis B surface antigen while recipients were unimmunized. Half of the allogeneic recipients were immunosuppressed with cyclosporin A. All animals were monitored weekly for the presence of anti-hepatitis B surface antibodies (anti-HBs). Effective anti-HBs titres were detected in 85% (29/34) of liver recipients and lasted from 2 to 10 weeks. Donor titre above >15 000 mIU/mL ensured a 100% seroconversion rate in the recipients. The maximal anti-HBs titre in recipients represented 0.06% approximately 0.76% of the donor titre. Rejection reduced the adoptive immune transfer, which was protected by immunosuppression. These observations suggest that transfer of functionally active donor lymphocytes, deriving from the graft, contributed to the donor-derived immune response in the recipient. Further studies to augment the donor-derived immune response are warranted to ensure a therapeutic effect for the recipient at risk of reinfection.

Animals↗

Cancer prevention by adoptive transfer of antigen 60-activated immunocompetent cells.

The authors have already shown that A60, the thermostable macromolecular antigen complex of Mycobacterium bovis BCG, induced resistance to tumour challenge in several murine systems. In the present work, the authors provided evidence that activated macrophages played a major role, and cytolytic T lymphocytes a minor one, in both in vivo and in vitro A60-promoted cancer cell cytolysis. To identify the types of immunocompetent cells involved in this protective effect, macrophages and T lymphocytes from A60-primed mice donors were adoptively transferred to irradiated recipients prior to EMT 6 tumour challenge. In some groups, A60-primed donors were survivors of previous tumour challenges. Transfer of T lymphocytes from the spleen or lymph-nodes of A60-immunized mice induced 80-90% protection against tumour challenge. Conversely, transferred macrophages, although cytolytically active, did not induce resistance to tumour implantation. Furthermore, adoptive transfer with T lymphocytes from A60-immunized and EMT 6 challenge-surviving donors induced 100% protection. It is concluded that stimulation of T lymphocytes by A60 is the key step which leads to activation of the immunocompetent cells involved in tumour rejection.

Animals↗

Infiltration patterns of short- and long-term cultured A-NK and T-LAK cells following adoptive immunotherapy.

Direct contact between lymphokine-activated killer (LAK) cells and tumour cells is believed to be imperative for initiating tumour cell lysis in vitro as well as in vivo. In order to optimize adoptive immunotherapy (AIT) it is therefore desirable to identify the LAK cell subtype, which ensures maximal infiltration of tumours as well as a substantial cytotoxic reactivity. In this report we have compared short- and long-term cultured murine adherent natural killer (A-NK) cells and mitogen-stimulated, lymphokine-activated T-killer (T-LAK) cells with respect to their proliferative potential, cytotoxicity, requirement for interleukin-2 (IL-2) and ability to infiltrate B16 pulmonary metastases following adoptive transfer. We found that short-term (5 days) cultured A-NK and T-LAK cells both showed a substantial accumulation of tumour tissues. However, A-NK cells gradually lost this ability during in vitro culture whereas T-LAK cells cultured for as long as 20 days retained their ability to infiltrate metastases as efficiently as their short-term cultured counterparts. Moreover, the low requirement of IL-2 by T-LAK cells to achieve maximal infiltration of tumours sharply contrasted with the excessive doses necessary to ensure maximal infiltration by A-NK cells. In conclusion, these data demonstrate that short-term cultured LAK cells of both NK- and T-cell origin are able to infiltrate B16 pulmonary metastases effectively. Importantly, the T cells retain this ability for a considerably longer time and require much less IL-2 support than do A-NK cells, making T-LAK cells attractive for AIT.

Animals↗

Collection of MNCs with two cell separators for adoptive immunotherapy in patients with stage IV melanoma.

BACKGROUND: MNCs for adoptive immunotherapy may be collected by leukocytapheresis with a cell separator. STUDY DESIGN AND METHODS: Six healthy cytapheresis donors donated two MNC concentrates on a cell separator (AS.TEC 204, Fresenius): one on the standard MNC program and one on a modified MNC program with reduced centrifuge velocity that leads to a lower platelet contamination. Seventeen patients with malignant melanoma donated 26 MNC concentrates: 5 on the AS.TEC 204 MNC program, 9 on the modified AS.TEC 204 MNC program, and 12 on another modified MNC program (Spectra, COBE). RESULTS: In the course of cultivation of MNCs to dendritic cells (DCs), the donor MNC concentrates with the lower platelet contamination (475 +/- 85 x 10(9)/L) had a significantly higher relative DC yield (low platelet contamination: 3.9 +/- 1.6% of the plated cells; high platelet contamination: 2.5 +/- 1.8% of the plated cells; p = 0.019) than the concentrates with the higher platelet contamination (2364 +/- 448 x 10(9)/L). No significant difference was found in the yields of MNCs and CD14+ cells in the three protocols used for the collection of MNCs from patients with melanoma. The components obtained by the standard AS.TEC 204 MNC program had a significantly higher platelet contamination (1768 +/- 994 x 10(9)/L) than the components obtained by the modified AS.TEC MNC program (360 +/- 98 x 10(9)/L; p<0.05) and the modified Spectra MNC program (636 +/- 266 x 10(9)/L); p<0.05). Because of the low number of investigated components, no significant difference in the DC yield of the three protocols could be detected (mean DC yield after cultivation: 746 +/- 429 x 10(6)). CONCLUSION: A high platelet contamination of MNC concentrates intended for adoptive immunotherapy can lead to a significant impairment of the DC yield after cultivation. Both the modified AS.TEC 204 and the modified Spectra MNC programs are well suited for collecting MNC concentrates with high MNC yields and low platelet contamination from patients with malignant melanoma.

Adult↗

The adult antisocial syndrome with and without antecedent conduct disorder: comparisons from an adoption study.

DSM antisocial personality disorder (ASPD) requires a retrospective diagnosis of conduct disorder-historical behavior not present in everyone with adult ASPD criteria. Using adoption study data, we examined the impact of this requirement on biological and environmental risk associations. We also compared clinical correlates of adult antisocial behavior with and without prior conduct disorder. We defined three subgroups: DSM-III ASPD (n = 30), adult antisocials without conduct disorder (n = 25), and controls (n = 142). By design, the sample had a high incidence of biological parent ASPD, which was partially confounded with fetal alcohol exposure. We compared the associations of both of these putative risk factors with subgroup membership after controlling for gender and adverse adoptive environment. We also examined differences in two sociopathy scales and the incidence of co-occurring affective, alcohol, and other substance use disorders. Finally, we explored differences in individual antisocial symptoms. Having an antisocial biological parent was a specific risk factor for ASPD. In contrast, fetal alcohol exposure, male gender, and adverse environment were associated with the adult antisocial syndrome, regardless of conduct disorder history. The two antisocial groups were similar with respect to sociopathy scales, co-occurring diagnoses, and the incidence of most individual symptoms. However, several adult and conduct disorder symptoms had significant specific associations with biological or environmental background or their interaction. Phenotypic expression of the biological-possibly genetic-risk for ASPD appears to be manifest before adulthood. The influence of other risk factors may not depend on antecedent conduct disorder. Despite this, we could not detect clinically important differences between the two sociopathic groups. The conduct disorder requirement therefore may be more relevant to etiological than clinical understanding of adult antisocial behavior.

Adolescent↗

Chemo-immunotherapy and chemo-adoptive immunotherapy of cancer.

The chemo-immunotherapy (CIT) and chemo-adoptive immunotherapy (CAIT) regimens tested in the past decade are summarized. From them we have learned a great deal about the interactions between various chemotherapeutic agents, immune modulating agents and effector cells. The most commonly reported result in multi-modality experiments with CAIT has been a synergistic enhancement in antitumor activity. Clinical trials usually demonstrated improvement in patient quality of life, an extension of survival time, and occasional complete regression of tumor. In many animal models, this enhancement often meant the complete regression and apparent cure of tumor in the animal. One mechanism by which this synergistic enhancement takes place appears to be a suppression of tumor-associated suppressor T cell activity by the chemotherapeutic agents, thereby inducing enhanced cytolytic activity against tumor by the adoptively transferred, activated effector cells. In CAIT the most commonly used drug has been cyclophosphamide. In CIT a wide variety of chemotherapy agents have been used but none of the clinical trials made use of cyclophosphamide. Thus, direct comparisons are not possible. Suggestive of the intricate regulatory processes involved, many CIT studies indicate a synergy only when specific doses of chemotherapy and immunotherapy agents are given, and in a specific sequence. CIT has become less toxic, is being handled on a cost-effective outpatient basis, while maintaining similar objective response rates to earlier inpatient treatments. In the future, CAIT and CIT will probably have an increasing role in the management of patients with specific cancers.

Animals↗

[Adoptive transfer of Epstein-Barr virus-specific T-lymphocytes in chronic active Epstein-Barr infection].

HISTORY: A 27-year-old man was admitted because of intermittent fever, fatigue, lymphadenopathy and splenomegaly for 20 years. Chronic administration of 6 - 8 g aspirin per day (self-prescribed) resulted in limited control of symptoms and in the development of analgesic nephropathy. INVESTIGATIONS: The patient had prominent splenomegaly and lymphadenopathy without histological signs of malignancy. Monocytosis and T-lymphopenia were also present. Infectious disease testing revealed IgG+/IgM- EBV serology and EA-EBV-mRNA nested PCR clearly demonstrated the presence of lytic EBV-proteins in PBMCs. TREATMENT AND COURSE: As chronic active Epstein-Barr virus infection (CAEBV) was highly probable, treatment with aciclovir, gancilovir and steroids was started. Because treatment failed adoptive T-cell transfer with autologous EBV-specific T-cells was performed. After three consecutive infusions the patient responded with a complete remission of fever, fatigue, lymphadenopathy and splenomegaly without adverse effects. Retrospective real-time PCR analysis showed a decrease in viral load from 62847 copies/ microg DNA to 45 - 250 copies after treatment. The patient remains in stable remission without signs of CAEBV (> 4 years). CONCLUSION: Adoptive transfer of autologous, EBV-specific T-lymphocytes is a promising treatment in CAEBV.

Acyclovir↗

Five years later: language in school-age internationally adopted children.

This study followed a cohort of 46 school-age children adopted from Eastern Europe who were originally studied by Glennen and Masters up through age 2 or 3. Five years later, the children were 6 to 9 years of age. Data on their school-age abilities were collected through surveys of parents and teachers. Parents indicated that 17.4% of the children were receiving classroom accommodations or special education programs and 54.5% had one or more diagnoses. The most common diagnosis was attention deficit disorder/attention deficit hyperactivity disorder (ADD/ADHD), occurring in 25% of the children, primarily boys. Learning disability and speech language impairment were each noted in 11.4% of the children. Language and Social Skill profiles on the Children's Communication Checklist-2 and Social Skills Rating Scale (SSRS) indicated that structural and meaning-based language abilities were areas of strength. Measures of pragmatic use of language (i.e., Use of Context, Social Relations, Nonverbal Communication) were relative weaknesses. Behavior profiles on the SSRS indicated higher than average levels of hyperactivity. The profile of Language and Social Skills strengths and weaknesses was similar to patterns observed in children with ADD/ADHD. Age of adoption was not predictive of school-age outcomes on these measures, but the children's expressive vocabulary when they were 2 to 3 years of age predicted SSRS outcomes for Social Skills and Problem Behaviors.

Acculturation↗

Adoptive cellular immunotherapy with CD19-specific T cells.

BACKGROUND: No effective therapeutic modalities exist for the treatment of relapsed high risk acute lymphoblastic leukemia (ALL). Adoptive cellular immunotherapy by transfusion of polyclonal donor lymphocytes is not always effective and is limited by cellular cross-reactivity with normal tissues, leading to development of clinical graft-versus-host disease (GVHD). METHOD: To develop an immunotherapeutic strategy for targeted elimination of residual leukemic blasts, human T cells were gene-modified to express CD19-specific chimeric receptors. RESULTS: Gene-modified T cells specifically lyse CD19-expressing lymphatic blast cells, however, they show a limited proliferative response to stimulation with CD19. Integration of the signal transduction domain of the costimulatory molecule CD28 enhances the proliferative properties of the gene-modified T cells. CONCLUSIONS: Adoptive transfer of gene-modified virus-specific T cells may provide a useful strategy for prevention and early treatment of ALL relapses following allogeneic stem cell transplantation.

Antigens, CD19↗

An adoption study of human obesity.

We examined the contributions of genetic factors and the family environment to human fatness in a sample of 540 adult Danish adoptees who were selected from a population of 3580 and divided into four weight classes: thin, median weight, overweight, and obese. There was a strong relation between the weight class of the adoptees and the body-mass index of their biologic parents - for the mothers, P less than 0.0001; for the fathers, P less than 0.02. There was no relation between the weight class of the adoptees and the body-mass index of their adoptive parents. Cumulative distributions of the body-mass index of parents showed similar results; there was a strong relation between the body-mass index of biologic parents and adoptee weight class and no relation between the index of adoptive parents and adoptee weight class. Furthermore, the relation between biologic parents and adoptees was not confined to the obesity weight class, but was present across the whole range of body fatness - from very thin to very fat. We conclude that genetic influences have an important role in determining human fatness in adults, whereas the family environment alone has no apparent effect.

Adoption↗

Intrathymic alloantigen-mediated, tolerant, completely major histocompatibility complex-mismatched mouse hearts are specifically rejected by adoptively transferred anti-class I L(d+)-specific 2C cells.

BACKGROUND: Tolerance to cardiac allografts can be induced in mice and rats by the injection of donor alloantigen into the thymus in combination with a CD4 T-cell-depleting antibody. CD8(+) cells in these animals are hyporesponsive to graft-specific alloantigens. Most of the CD8(+) T cells in the transgenic 2C mouse express a T-cell receptor specific for the class I major histocompatibility complex L(d+) locus. This study was designed to determine whether the adoptive transfer of these 2C T cells could precipitate rejection of a tolerant, completely major histocompatibility complex-mismatched L(d+) or L(d-) heart. METHODS: C57BL/6 mice (L(d-)) were given 10 x 10(6) cells of BALB/c (L(d+)) or dm2 (BALB/c background lacking L(d) [L(d-)]) splenocytes intrathymically and GK1. 5 (10 mg/kg) intraperitoneally. Twenty-one days later, BALB/c or dm2 hearts were transplanted. On the day of transplantation or after long-term allograft acceptance, recipients received naive 2C cells or 2C cells sensitized by in vitro mixed lymphocyte culture with BALB/c (L(d+)). RESULTS: Mean survival time of BALB/c cardiac allografts in untreated C57BL/6 mice was 7.3 days, although 73% of the mice that were pretreated with BALB/c splenocytes IT plus GK1.5 accepted the donor antigen-specific heart allografts indefinitely. All recipients that were pretreated with the intrathymic plus GK1.5 and that were injected with naive 2C cells at the time of heart transplantation experienced rejection of the BALB/c (L(d+)), but not the dm2 (L(d-)) hearts. In contrast, naive 2C cells could not reject tolerant (>30 days acceptance) BALB/c (L(d+)) hearts. 2C cells sensitized in vitro against L(d) were able to reject established BALB/c hearts but could not reject the L(d-) dm2 hearts. CONCLUSIONS: L(d)-specific 2C T-cell receptor transgenic T cells that are adoptively transferred to recipients will precipitate the rejection of accepted hearts that express class I L(d+) in mice rendered tolerant by an intrathymic injection of alloantigen plus anti-CD4 monoclonal antibodies.

Adoptive Transfer↗