Adoptive transfer of mucosal T cells or dendritic cells from animals fed with cholera toxin B subunit alloantigen conjugate induces allogeneic T cell tolerance.
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Administration, Oral↗
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ADOPTIVE TRANSFER OF ANTIBODY PRODUCTION IN THE CHICK EMBRYO. 1. THE INOCULATION OF STIMULATED SPLEEN CELLS FROM ADULT FOWLS ON TO THE CHORIO-ALLANTOIC MEMBRANE OF OUTBRED AND INBRED EMBRYOS.
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Adoptive Transfer↗
A case report of immunotherapy on a patient with advanced gastric cancer by adoptive transfer of OK-432-reactive HLA-matched allogeneic lymphocytes.
Adoptive immunotherapy (AIT) for non-hematological malignancies, using HLA-matched donor lymphocytes, has been rarely reported. For a 35-year-old male patient with peritoneal disseminated advanced gastric cancer, we performed AIT using lymphocytes from his HLA-matched 37-year-old brother and a streptococcal preparation, OK-432, as an antigen. After the donor had been immunized by intradermal administration of OK-432, OK-432-reactive lymphocytes were induced in vitro and transferred to the patient intravenously with OK-432. Low-dose systemic immunochemotherapy, using interleukin-2, 5-fluorouracil and cyclophosphamide, was concurrently administered with AIT. As a result, the Schnitzler metastasis in the patient reduced in size without any significant graft-versus-host-related complications. One of the effector mechanisms of therapeutic benefit was suggested to be cytokine release from the transferred OK-432-reactive lymphocytes. Our findings suggest the safety and efficacy of AIT using lymphocytes from an HLA-matched sibling and OK-432 as an antigen. Further studies to investigate the use of tumor-associated antigen and an HLA-matched sibling's lymphocytes for AIT of advanced cancer are warranted.
Adenocarcinoma, Scirrhous↗
Adoptive transfer of regulatory T cells following chronic allograft rejection induces tolerance for secondary allografts.
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Adoptive Transfer↗
Adoptive transfer of myelin basic protein-tolerized splenocytes to naive animals reduces infarct size: a role for lymphocytes in ischemic brain injury?
BACKGROUND AND PURPOSE: Breakdown of the blood-brain barrier during stroke allows central nervous system antigens to leak into the systemic circulation and allows circulating leukocytes access to the brain. Encounter of central nervous system antigens by the peripheral immune system can be capitalized on to modulate the postischemic inflammatory response and potentially improve outcome from stroke. METHODS: Male Lewis rats were tolerized to myelin basic protein (MBP) or ovalbumin (OVA) and subjected to 3 hours of middle cerebral artery occlusion (MCAO) or used as splenocyte donors for immunologically naive animals undergoing MCAO. Infarct size was determined at 24 hours by 2,3,5-triphenyltetrazolium chloride staining. In separate studies, mononuclear cells were removed from the brains of animals after MCAO for enzyme-linked immunospot (ELISPOT) assay and flow cytometry. RESULTS: Median infarct volume in animals tolerized to MBP and those receiving splenocytes from MBP-tolerized donors was less than in animals tolerized to OVA and those receiving splenocytes from OVA-tolerized donors (87.7+/-54.9 versus 148+/-61.6 mm3 [P=0.01] and 89.2+/-77.5 versus 153+/-77.1 mm3 [P=0.05], respectively). There was an increase in the number of transforming growth factor-beta1-secreting mononuclear cells in MBP-tolerized animals undergoing sham surgery (P=0.001) as well as in ischemic animals 48 hours (P=0.02) and 336 hours (P=0.04) after stroke. A distinct subset of gammadelta T cells was present in the brains of MBP-tolerized but not control animals after stroke. CONCLUSIONS: Immunologic tolerance and its neuroprotective effects can be transferred to naive animals and appear to be related to antigen-specific induction of transforming growth factor-beta1.
Administration, Intranasal↗
Tumor infiltration by adoptively transferred T cells is independent of immunologic specificity but requires down-regulation of L-selectin expression.
Adoptive immunotherapy with anti-CD3/IL-2 activated tumor-draining lymph node (LN) T cells is capable of eradicating tumor established at various histological sites. Tumor-specific effector lymphocytes have recently been identified to be LN T cells with down-regulated L-selectin (L-selectin-). Using fluorochrome labeling, the present study determined the early trafficking pattern of systemically transferred cells. In mice with 10-day established pulmonary 3-methylcholanthrene (MCA) 205 metastases, accumulation of cells in tumors was evident as early as 2 h after i.v. cell transfer, and, by 24 h, >50-fold higher numbers of cells were seen in metastases than in normal tissues. Similarly, transferred cells selectively infiltrated s.c. tumors, albeit at a lower rate. Analysis of the transferred cells isolated from recipient mice revealed that tumor-infiltrating cells were mostly L-selectin- (>95%). By contrast, only 24% and 58% L-selectin- cells were found in the LN and spleen, respectively. The ability of L-selectin- cells to accumulate at tumor sites was confirmed by the transfer of purified cell populations. Despite this selective tumor infiltration, the trafficking pattern did not reflect antigenetic specificity, and tumor regression occurred only after the transfer of tumor-specific effector cells. These results, thus, suggest that there are two distinct mechanisms operative in successful adoptive immunotherapy. Early infiltration of tumors by transferred cells is dictated by the physiological properties of cells and is independent on their immunologic specificity. Tumor regression, however, requires immunologically specific interactions at the site of tumor.
Adoptive Transfer↗
Mechanisms of acquired tolerance induced by adoptive transfer of MHC-specific alloreactive T cells: effector T cells migrate to the thymus.
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Adoptive Transfer↗
Adoptive transfer of alveolar macrophages abrogates bronchial hyperresponsiveness.
Increasing evidence suggests that alveolar macrophages (AM) are involved in asthma pathogenesis. To better understand the role that these cells play, we investigated the capacity of AM from allergy-resistant rat, Sprague Dawley (SD), to modulate airway hyperresponsiveness of allergy-susceptible rat, Brown Norway (BN). AM of ovalbumin (OVA)-sensitized BN rats were eliminated by intratracheal instillation of liposomes containing clodronate. AM from OVA-sensitized SD rats were transferred into AM-depleted BN rats 24 h before allergen challenge. Airway responsiveness to methacholine was measured the following day. Instillation of liposomes containing clodronate in BN rats eliminated 85% AM after 3 d compared with saline liposomes. Methacholine concentration needed to increase lung resistance by 200% (EC200RL) was significantly lower in OVA-challenged BN rats (27.9 +/- 2.8 mg/ml) compared with SD rats (63.9 +/- 8.6 mg/ml). However, when AM from SD rats were transferred into AM-depleted BN rats, airway responsiveness (64.0 +/- 11.3 mg/ml) was reduced to the level of naïve rats (54.4 +/- 3.7 mg/ml) in a dose-dependent manner. Interestingly, transfer of AM from BN rats into SD rats did not modulate airway responsiveness. To our knowledge, this is the first direct evidence showing that AM may protect against the development of airway hyperresponsiveness.
Adoptive Transfer↗
Cutaneous delayed type hypersensitivity in SCID mice adoptively transferred with lymphocytes is B cell independent and H-2 restricted.
Severe combined immunodeficiency (SCID) mice are largely devoid of functional T and B lymphocytes but have normal antigen presenting cell (APC) capacity. The authors have examined the requirements for cutaneous delayed type hypersensitivity (DTH) in SCID recipients by i.p. transfer of freshly isolated naive mature. T cells or non-fractionated spleen cells of H-2 compatible or incompatible origin. Recipient SCID mice were epicutaneously sensitized with oxazolone (OXA) within 24 h after cell transfer. SCID mice injected with as few as 10(5) H-2 compatible BALB/c (H-2d) spleen cells were able to mount DTH ear swelling reaction upon sensitization and challenge with OXA. Non-fractionated spleen cells from H-2 incompatible B6 or NZW mice were also able to restore DTH capacity in SCID recipients. However, when thymocytes were transferred, only donor mice expressing H-2d, but not H-2b and H-2z, haplotype restored DTH reactivity. Serum levels of IgM and IgM anti-OXA antibodies in SCID mice 27 days post-transfer with 10(7) BALB/c spleen cells were similar to that of intact donor mice. In contrast, specific antibodies of IgG isotype were approximately only one-tenth of that found in BALB/c controls. The results of this study show that for the development of cutaneous DTH, in SCID mice transferred with T cells, H-2 restricted APC-T cell interaction is required, whereas B cells are not mandatory. Also, SCID mice transferred with splenocytes show signs of defect immunoglobulin switch function. The authors believe that this model of DTH will be useful in delineating the effects of immunomodulatory substances in vivo on distinct host versus donor cell populations.
Adoptive Transfer↗
Characteristics of rat CD4(+)CD25(+) T cells and their ability to prevent not only diabetes but also insulitis in an adoptive transfer model in BB rats.
Human and mouse CD4(+)CD25(+) T cells have been intensively studied through the last decade. However, little is known about this subset in other species. This study describes the phenotype of rat CD4(+)CD25(+) Foxp3(+) T cells and the site in which they exert regulation in a transfer-induced autoimmune diabetes model. Several proteins and mRNAs are up-regulated in unstimulated rat CD4(+)CD25(+) T cells compared with CD4(+)CD25(-) T cells, including Foxp3, Lag-3, CD80, interleukin 10 (IL-10) and CTLA-4. To investigate CD4(+)CD25(+) T cells in vivo, we transferred three million diabetogenic T cells either alone or in combination with two million CD4(+)CD25(+) T cells to 30-day-old BB rats. The pancreas and the pancreatic lymph nodes were examined as two potential regulatory sites. Time-course analysis of pancreatic histology following diabetogenic T-cell transfers revealed insulitis from about 14 days after transfer. By contrast, rats receiving both diabetogenic T cells and CD4(+)CD25(+) T cells had no insulitis at any time. Moreover, the frequency of diabetogenic T cells in the pancreatic lymph nodes 2 days after transfer was significantly reduced in rats receiving both subsets. These data indicate that the primary site of T-cell regulation is in the draining lymph nodes and not the pancreas in our model.
Adoptive Transfer↗
Adoptive transfer of tumor cytotoxic macrophages generated in vitro from circulating blood monocytes: a new approach to cancer immunotherapy.
Cells of the macrophage lineage are considered to be of special importance in the defense of the host against tumor development and spread. Immunotherapeutic strategies to stimulate macrophage (MAC) tumor cytotoxicity make use of activating compounds such as gamma-interferon which are given systemically. However, there are several lines of evidence that in malignant disease the generation of cytotoxic effector MACs is impaired. Both defective cell maturation and loss of responsiveness to activation are described. Here, a first clinical phase I trial of adoptive immunotherapy in cancer patients using autologous MACs generated in vitro from blood monocytes (MOs) is reported. Mononuclear cells were isolated by cytapheresis and density centrifugation and cultured in hydrophobic Teflon bags for 7 days with 2% autologous serum and recombinant human gamma-interferon being present for the last 18 h. Cytotoxic MO-derived MACs were then purified by countercurrent elutriation and reinfused into the patient. A total of 72 therapies have been performed with patients being treated i.v. (n = 8) and i.p. (n = 7). In vitro generated MACs proved to be mature as judged by the expression of maturation-associated surface molecules (MAX antigens, CD16, CD51, CD71), were cytotoxic to U937 tumor cells, and were efficient secretory cells. Cell dose escalation was performed in the first patients beginning with 10(8) MACs to finally infuse the total number of cells recovered from one single cycle of isolation and culture. MAC yield varied from 1 to 17 x 10(8) representing 13-79% of MOs initially seeded. Adoptive MAc transfer was well tolerated. Side effects observed were low-grade fever (less than 38.5 degrees C), induction of the coagulation cascade, and abdominal discomfort after i.p. application. The procoagulant activity of MAC autografts was cell dose dependent and demonstrated by detection of circulating fibrin monomers and thrombin-antithrombin complexes. Biological responses observed included elevated serum neopterin levels and the appearance of interleukin-6 in sera and ascitic fluids. Indication of a possible therapeutic effect was only observed in i.p.-treated patients and consisted of disappearance of malignant ascites in 2 of 7 patients.
Adult↗
Adoptive transfer of genetically modified macrophages elucidated TGF-beta-mediated 'self-defence' of the glomerulus against local action of macrophages.
TGF-beta has several anti-inflammatory properties which may be relevant to prevention of or recovery from acute glomerular inflammation. Using genetically modified mesangial cells and a technique for in vivo macrophage transfer, this article provides evidence for TGF-beta-mediated 'self-defence' of the glomerulus against macrophages. Rat mesangial cells stably transfected with TGF-beta1 showed a blunted response to the macrophage-derived, proinflammatory cytokine IL-1beta. In contrast, mesangial cells expressing the dominant-interfering TGF-beta receptor showed an enhanced response to IL-1. Similarly, externally added TGF-beta1 inhibited the cytokine response of normal glomeruli, and isolated nephritic glomeruli producing active TGF-beta1 showed a depressed response to IL-1beta, compared to normal glomeruli. Consistent with these in vitro results, in vivo transfer of activated macrophages revealed that the TGF-beta-producing glomeruli are insensitive to the effector action of macrophages. These results indicate that TGF-beta1 functions as an endogenous 'defender' that counteracts local action of activated macrophages in the glomerulus.
Adoptive Transfer↗
Continuous nasal administration of antigen is critical to maintain tolerance in adoptively transferred autoimmune arthritis in SCID mice.
Mucosal tolerance is a natural mechanism that prevents immunological reactions to antigens by altering the activity of immune cells of pathogenic clones without modulating the entire immune system. This 'natural immune suppression' can be exploited when antigen(s) of the target organ in an autoimmune disease is used for mucosal treatment. Being inspired by the experimental results in animal models, clinical trials using type II collagen for mucosal treatment have been conducted in rheumatoid arthritis. High-density proteoglycan (aggrecan) is another major macromolecular component in articular cartilage, and may be a candidate autoantigen for provoking immune reactions in patients with rheumatoid arthritis. Indeed, like type II collagen, systemic immunization of genetically susceptible mice with proteoglycan (PG) aggrecan induces progressive autoimmune polyarthritis. Here, we investigated whether intranasally applied PG can be effective in suppressing PG-induced arthritis (PGIA) in BALB/c mice. We found that nasal administration of 100 microg PG exerted a strong suppressive effect on both the incidence and severity of the disease, most probably by reducing responsiveness towards the immunizing PG antigen. When we transferred PGIA into genetically matched but immunodeficient SCID mice, we were able to establish a tolerized state, but only if the recipient SCID mice received lymphocytes from tolerized animals and intranasal treatment with PG was continued. Without nasally administered antigen, the transferred anergic cells recovered and arthritis rapidly developed in a severe form. Intranasal PG treatment of recipient SCID mice was ineffective when cells from non-tolerized arthritic donors were transferred, in which case the regular weekly 'tolerizing' dose of PG made the disease worse. Our results suggest that mucosal treatment in an already existing disease may result in paradoxical outcomes.
Administration, Intranasal↗
The subpopulation of CD4+CD25+ splenocytes that delays adoptive transfer of diabetes expresses L-selectin and high levels of CCR7.
Recently, CD4(+)CD25(+) T cells have been implicated in the control of diabetes, suggesting that the inflamed islets of Langerhans in prediabetic NOD mice are under peripheral immune surveillance. Here we show that CD4(+)CD25(+) splenocytes inhibit diabetes in cotransfer with islet-infiltrating cells. Furthermore, CD62L expression is necessary for this disease-delaying effect of CD4(+)CD25(+) cells in vivo, but not for their suppressor function in vitro. We demonstrate that the CD4(+)CD25(+)CD62L(+) splenocytes express CCR7 at high levels and migrate toward secondary lymphoid tissue chemokine and ELC (macrophage-inflammatory protein-3beta), lymphoid chemokines, whereas CD4(+)CD25(+)CD62L(-) splenocytes preferentially express CCR2, CCR4, and CXCR3 and migrate toward the corresponding inflammatory chemokines. These data demonstrate that CD4(+)CD25(+)CD62L(+), but not CD4(+)CD25(+)CD62L(-), splenocytes delay diabetes transfer, and that CD4(+)CD25(+) suppressor T cells are comprised of at least two subpopulations that behave differently in cotransfer in vivo and express distinct chemokine receptor and chemotactic response profiles despite demonstrating equivalent suppressor functions in vitro.
Adoptive Transfer↗
In vivo persistence of donor cells following adoptive transfer of allogeneic dendritic cells in HIV-infected patients.
Peripheral blood samples from HIV-seropositive individuals enrolled in a pilot clinical trial investigating the use of allogeneic dendritic cell therapy were evaluated for mixed chimerism. In this study, dendritic cells from HLA-identical, HIV-seronegative siblings were used. Patients received an infusion of dendritic cells pulsed with HIV MN gp160 protein or with peptides from HLA-A2 restricted epitopes of env, gag, and pol proteins every month for 6-9 months. Of the five allogeneic dendritic cell recipients, two showed increases in HIV antigen-specific immune responses. Allele-specific polymorphisms were identified in three sib-pairs that allowed infused donor cells to be detected using sensitive PCR-based molecular methods. Analysis of blood samples from patients showed similar patterns of donor cell persistence after the first infusion, in that cells were detectable for at least 1 week. Also, differences were observed in the kinetics of cell survival between the first and subsequent infusion cycles in all three patients. This suggests variation in HIV-specific immune responses detected among these three patients was not due to differences in persistence of infused donor cells.
Adoptive Transfer↗
Adoptive transfer of a Th2-like cell line prolongs MHC class II antigen disparate skin allograft survival in the mouse.
The MHC class II alloantigen-reactive CD4+ Th2-like cell line, HR2, was established. It was derived from the spleen cells of C57BL/6 (B6) mice immune to an MHC class II-disparate mutant mouse, B6.CH-2bm12 (bm12) which carries the I-Abm12 antigen. This cell line, HR2, secretes IL-4 and IL-10 in an antigen-specific manner, and can also proliferate in an autocrine manner through IL-4. To investigate the in vivo role of this Th2-like CD4+ T cell line in transplantation immunity, an adoptive cell transfer study using the skin allograft system was performed. Skins grafted from bm12 to B6 were rejected at 12.1 +/- 0.6 days in control B6 mice which received no treatment. Whereas skin graft survival was prolonged in B6 experimental mice which had received 2 x 10(7) HR2 cells, 75% of the grafts survived for > 40 days. Moreover, since skin grafts from fully allogeneic third party donor BALB/c mice were rejected at 12.0 +/- 0.4 days by B6 mice which had received the same number of HR2 cells, it was demonstrated that HR2 is involved in the regulation of bm12 skin graft rejection. Furthermore, cytotoxic T lymphocyte (CTL) activity by spleen cells from HR2 transferred B6 mice was not induced even by in vitro secondary stimulation, although CTL activity was induced well in spleen cells of control B6 mice which had rejected the graft. The underlying mechanism has not been fully clarified; however, these results demonstrate that Th2-like CD4+ T cells suppress allograft rejection.
Animals↗
Growth retardation of tumors by adoptive transfer of cytotoxic T lymphocytes reprogrammed by CD44v6-specific scFv:zeta-chimera.
Variants of the CD44 protein family containing sequences encoded by variant exon 6 (v6) are involved in the metastatic spread of rat and human tumors. The rat-specific antibody 1.1ASML, which recognizes a v6 epitope, interferes with metastatic dissemination of a rat pancreatic carcinoma. The single-chain antigen-binding fragment of this monoclonal antibody was fused to the zeta-chain of the T-cell receptor complex. The appropriate fusion gene was incorporated into a retroviral gene transfer vector. Murine cytotoxic T lymphocytes (CTLs) were infected, and cellular clones which express the single-chain zeta-chain fusion protein on their cell surface were selected. These CTLs are not MHC-restricted in their CD44v6 recognition and exhibit in vitro lytic activity toward cells expressing CD44 variants comprising exon v6. Tumor cell xenografts grown in athymic nude mice are suppressed in their growth upon infusion of the genetically manipulated CTLs. Our data indicate that the CD44v6 epitope is an effective target for immune tumor therapy and demonstrate the efficacy of genetically engineered CTLs in targeting tumors expressing such epitopes.
Adoptive Transfer↗
[Cardiac impairments induced by adoptive transfer of lymphocytes from the experimental cardiomyopathy in mice].
OBJECTIVE: To investigate the autoimmune mechanism in dilated cardiomyopathy (DCM). METHODS: Thirty-six male Balb/c mice were randomly divided into 2 groups: DCM group to be immunized with human mitochondrion ADP/ATP vector polypeptides and control group (sham immunization group) to be injected with immune fluid without the polypeptide. Before the injection and then every month after the injection serum was collected to examine the ADP/ATP autoantibody level by ELISA. One month after immunization 6 mice of each group were killed and 6 months after the remaining mice were all killed to undergo serologic and histological examination. Lymphocytes from spleen were collected from the mice injected with ADP/ATP vector polypeptides, some of these spleen lymphocytes were co-cultured with concanavalin A (ConA) and some were cultured without stimulation of ConA. Six months after the ADP/ATP vector polypeptide injection another 24 Balb/c mice were randomly divided into 2 groups: DCM-T-A group to be injected with the spleen lymphocytes stimulated by ConA and DCM-T group to be injected with the spleen lymphocytes without ConA stimulation. One month after the transfer 6 mice of each group were killed and 6 months after the remaining mice were all killed to undergo serologic and histological examination. RESULTS: One month and 6 months after immunization autoantibody against ADP/ATP vector was positive in the sera of the mice in both DCM and DCM-T-A groups. One month after immunization or transfer the myocardium of both DCM and DCM-T-A groups showed myocarditis-like changes, and 6 months after immunization or transfer the myocardium of both DCM and DCM-T-A groups showed DCM-like changes. Increase of different cytokines was found in the myocardium in both DCM and DCM-T-A groups with predominance of interferon-gamma and interleukin (IL)-2 one month after and predominance of IL-4, IL-6, and tumor necrosis factor-alpha 6 months after immunization or transfer. Such changes were not found in the control group and DCM-T group. CONCLUSION: Human mitochondria ADP/ATP peptides induce autoimmune DCM in mice. T cell-mediated responses play an important role in the development of DCM.
Adoptive Transfer↗