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PubMed2000

Interleukin 7 is a potent co-stimulator of myelin specific T cells that enhances the adoptive transfer of experimental autoimmune encephalomyelitis.

Interleukin 7 (IL-7), originally described as a B cell growth factor, has recently been found to play a critical role in T and B lymphocyte development and function. This study evaluated the effects of IL-7 on myelin specific T cells. IL-7 strongly enhanced proliferation of proteolipid protein (PLP) 139-151 specific T cells in association with elevated secretion of the T cell growth factor IL-2. Co-stimulation with IL-7 preferentially increased the levels of pro-inflammatory cytokines secreted by PLP 139-151 specific T cells and adoptive transfer of these cells into naive recipients induced a profound enhancement of experimental autoimmune encephalomyelitis, an animal model for the human disease multiple sclerosis. These results suggest that IL-7 may be a critical co-stimulatory factor that enhances the extrathymic expansion of inflammatory T cells and may play an important role in the pathogenesis of a number of inflammatory autoimmune disorders.

Adoptive Transfer↗
PubMed2003

Investigating the impact of helminth products on immune responsiveness using a TCR transgenic adoptive transfer system.

Helminth infections and their products have a potent immunomodulatory effect on the host immune system and can impair immune responses against unrelated Ags. In vitro studies have suggested that the immunomodulation by helminth extracts may be the result of bystander response bias toward a Th2 phenotype and/or an Ag-specific T lymphocyte proliferative hyporesponsiveness. The aim of this study was to determine the role of these potential mechanisms of immunosuppression in vivo. Therefore, using a sensitive model of CFSE-labeled OVA-specific TCR transgenic T lymphocyte adoptive transfer, we analyzed the effect of Ascaris suum body fluid (ABF) on the kinetics and amplitude of a primary OVA-specific T cell response as well as the Th1/Th2 profile of the response in wild-type and IL-4 knockout (KO) mice. We find that inhibition of delayed-type hypersensitivity by ABF was associated with a Th1/Th2 shift in wild-type animals, but not in IL-4 KO mice. The use of this model has allowed us to demonstrate that although the kinetics of the OVA-specific primary response was not affected by ABF, the expansion of the OVA-specific T lymphocytes was significantly inhibited in both wild-type and IL-4 KO mice. This inhibition was associated with a reduced proliferative capacity of these cells in vivo, distinct from anergy.

Adoptive Transfer↗
PubMed2003

Pharmacologically regulated Fas-mediated death of adoptively transferred T cells in a nonhuman primate model.

Conditional suicide genes derived from pathogens have been developed to confer drug sensitivity and enhance safety of cell therapy, but this approach is limited by immune responses to the transgene product. We examined a strategy to regulate survival of transferred cells based on induction of apoptosis through oligomerization of a modified human Fas receptor by a bivalent drug (AP1903). Three macaques (Macaca nemestrina) received autologous T cells retrovirally engineered to express a Fas suicide-construct (LV'VFas). High levels of transduced cells were present in blood following cell transfer, but LV'VFas(+) cells declined rapidly after AP1903 administration. A small fraction of LV'VFas(+) cells resisted elimination by AP1903, in part due to insufficient levels of transgene expression in resting T cells, because reactivation of these cells in vitro enhanced sensitivity to AP1903. An immune response to the transgene product was observed, but epitope mapping indicated the response was directed to discrete components of human LV'VFas that were variant with the corresponding macaque sequences. These data demonstrate that chemically induced dimerization can be used to regulate survival of adoptively transferred T cells in vivo.

Adoptive Transfer↗
PubMed1996

Immunization with soluble BDC 2.5 T cell receptor-immunoglobulin chimeric protein:antibody specificity and protection of nonobese diabetic mice against adoptive transfer of diabetes by maternal immunization.

The BDC 2.5 T cell clone is specific for pancreatic beta-cell antigen presented by I-Ag7, and greatly accelerates diabetes when injected into 10-21-d-old nonobese diabetic (NOD) mice. The BDC 2.5 T cell receptor (TCR) has been solubilized as a TCR-IgG1 chimeric protein. All NOD mice immunized against BDC 2.5 TCR-IgG1 produced antibodies recognizing TCR C alpha/C beta epitopes that were inaccessible on the T cell surface. 56% of the mice produced antibodies against the BDC 2.5 clonotype that specifically blocked antigen activation of BDC 2.5 cells. We have used the adoptive transfer model of diabetes to demonstrate that maternal immunization with soluble TCR protects young mice from diabetes induced by the BDC 2.5 T cell clone.

Adoptive Transfer↗
PubMed1995

Longer local retention of adoptively transferred T-LAK cells correlates with lesser adhesion molecule expression than NK-LAK cells.

The local retention of adoptively transferred lymphokine (IL-2)-activated killer (LAK) cells was examined in 11 patients with head and neck carcinoma. Unseparated lymphocytes, T and natural killer (NK) cells isolated from patients were cultured with IL-2 for 7 days, labelled with 99mTc-HMPAO, and immediately injected back into the respective donors via the superficial temporal artery or locally into the tumour tissue. The injected LAK cells were periodically traced using a gamma camera, and the LAK cell retention rate was calculated from the radioactivity. One hour after the injection, about 70% of the locally infiltrated LAK cells remained in the tumour tissue, while about half of the LAK cells transferred via the regional artery were dislodged from the tissue. LAK cells induced from T cells (T-LAK) were retained in the tissue for a longer time than LAK cells induced from NK cells (NK-LAK). T-LAK were less chemotactic and less adherent to human umbilical vein endothelial cells (EC), and showed lesser migration through EC. Flow cytometric analysis revealed higher expression of CD11a, CD11b, CD18 and CD49d on NK-LAK compared with T-LAK. MoAbs against these adhesion molecules suppressed adhesion and migration of LAK cells. These results indicate that the rapid disappearance of NK-LAK from the tissue is associated with their greater chemotactic and adhesive as well as migratory activities depending on differing expression of adhesion molecules.

Adult↗
PubMed1975

Lymphoid cell dependence of eosinophil response to antigen. VI. The effect of selective removal of T or B lymphocytes on the capacity of primed spleen cells to adoptively transferred immunity to tetanus toxoid.

Spleens from mice primed with tetanus toxoid 30 days earlier contain memory cells capable of adoptively transferring secondary type cell-mediated (eosinophil) and humoral (antitoxin) responses to irradiated, reconstituted recipients. Spleen cells derived from 10-day-primed donors, on the other hand, possess the capacity after transfer to elicit secondary type eosinophil responses, but not anamnestic antitoxin responses. Treatment of 30-day-primed cells with anti-theta serum and C' prevented transfer of memory for both responses, whereas similar treatment with rabbit anti-mouse IgG (RAM-IgG) serum and C' only inhibited transfer of memory for the antitoxin response. Addition of non-primed spleen cells to antisera-treated primed cells failed to restore secondary type responses. Recombination of 30-day-primed anti-theta and RAM-IgG-treated cells re-established the capacity to transfer these responses. To determine whether the same T cells which mediate the eosiniphil response also act as helper cells in antitoxin production, antisera treated 10- and 30-day-primed cells were combined prior to transfer. Ten-day-primed T cells induced eisoniphil responses and also co-operated with 30-day-primed B cells to produce antitoxin. In contrast, 30-day-primed T cells elicited eisinophil responses, but were unable to induce antitoxin production when combined with anti-theta-treated 10-day-primed cells. These results indicate that B memory cells are not present in the spleens of the donor mice 10 days after priming, but T memory cells are present. It is concluded that primed T cells mediated both eosinophil and antitoxin responses, while B memory cells are involved only with antitoxin production. Following subcutaneous priming T memory cells are present in the spleen prior to B memory cells, and T memory cells which mediate the eosinophil response at 10 days after priming also augment the production of antitoxin by B memory cells.

Animals↗
PubMed2000

Dendritic cells armed with anti-CD3 mAbs reduce pulmonary metastases, prolong survival, and engender antitumor effector cells demonstrable by adoptive transfer.

BACKGROUND: Dendritic cells (DCs) pulsed with tumor cells or peptides are effective antitumor agents in a number of tumor models. In light of our earlier demonstration that T-cell signaling via the CD3 proteins induces cytolytic activity and constrains tumor progression, we equipped DCs pulsed with tumor cells with anti-CD3 mAbs and tested their antitumor efficacy in a murine renal cell cancer pulmonary metastasis model. METHODS: We investigated the antitumor efficacy of DCs pulsed with whole irradiated tumor cells (DC/R) or DCs pulsed with irradiated tumor cells and armed with anti-CD3 mAbs (DC/R/anti-CD3 mAbs). Experimental end points included the number of pulmonary metastases and survival of tumor-inoculated mice. RESULTS: Our studies demonstrate that arming tumor-pulsed DCs with anti-CD3 mAbs results in a superior outcome compared to that from tumor-pulsed DCs alone in terms of reduction in the number of pulmonary metastases and survival times. Furthermore, adoptive transfer experiments revealed that the splenocytes from DC/R/anti-CD3 mAbs-treated mice are superior to splenocytes from DC/R-treated mice in reducing renal cancer pulmonary metastases in severe combined immunodeficient (SCID) beige mice. CONCLUSION: Our data suggest that the therapeutic efficacy of DCs pulsed with tumor cells can be augmented by arming them with anti-CD3 mAbs. DC-based treatment regimens that currently are being pursued in clinical trials might be improved by equipping such cells with anti-CD3 mAbs.

Adoptive Transfer↗
PubMed2001

Antibody blockade of ICAM-1 and VCAM-1 ameliorates inflammation in the SAMP-1/Yit adoptive transfer model of Crohn's disease in mice.

BACKGROUND & AIMS: Integrins (alpha(4) and beta(2)) and their endothelial ligands vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) play key roles in leukocyte recruitment to areas of inflammation. ICAM-1 and VCAM-1 are expressed in inflamed intestinal tissues. This study investigates a possible causative role of adhesion molecules ICAM-1, VCAM-1, and alpha(4) integrins in mediating the inflammatory response in a murine model of Crohn's disease (CD). METHODS: CD4+ mesenteric lymph node cells from SAMP-1/Yit donor mice were adoptively transferred into major histocompatibility complex-matched severe combined immunodeficiency disease mice. Six weeks later, these mice were left untreated or treated for 3 days with monoclonal antibodies (mAbs) to ICAM-1, VCAM-1, or both, and alpha(4), or both ICAM-1 and alpha(4), dexamethasone, or nonblocking isotype control antibodies. On day 4 after treatment, tissues were investigated for expression of ICAM-1, VCAM-1, and for severity of inflammation using a semiquantitative inflammatory score. Dexamethasone treatment resolved all measures of intestinal inflammation. RESULTS: Blocking either ICAM-1, VCAM-1, or alpha(4) integrins had no significant beneficial effect. However, blocking ICAM-1 and alpha(4), or blocking ICAM-1 and VCAM-1, showed a 70% resolution of the active inflammation, but not chronic inflammation. CONCLUSIONS: These findings suggest that blocking ICAM-1 and VCAM-1 may have therapeutic benefit for the acute inflammatory component of Crohn's disease.

Adoptive Transfer↗
PubMed1997

Nonatopic asthma: in vivo airway hyperreactivity adoptively transferred to naive mice by THY-1(+) and B220(+) antigen-specific cells that lack surface expression of CD3.

To investigate the cellular immune events contributing to airway hyperreactivity (AHR), we studied an in vivo mouse model induced by the hapten picryl (trinitrophenyl) chloride (PCl). Mice were immunized by cutaneous contact sensitization with PCl and airway challenged subsequently with picryl sulfonic acid (PSA) antigen (Ag). Increased airway resistance was produced late (24 h) after Ag challenge, disappeared by 48 h, and was associated with no decrease in diffusion capacity. AHR could be produced in PCl immune/ PSA challenged mice on day 7 or even, with challenge, as early as 1 d after contact sensitization, after adoptive transfer of immune cells lacking CD3(+) contact sensitivity effector T cells, or after transfer of Ag-specific lymphoid cells depleted of conventional T lymphocytes with surface determinants for CD3, CD4, CD8, TCR-beta, or TCR-delta molecules. Further experiments showed that development of AHR depended upon transfer of immune cells expressing surface membrane Thy-1 and B220 (CD45RA) determinants. We concluded that a novel population of Ag-specific lymphoid cells with a defined surface phenotype (Thy-1(+), CD3(-), CD4(-), CD8(-), TCR-alphabeta-, TCR-gammadelta-, and CD45RA+) is required in a mouse model for the development of AHR.

Adoptive Transfer↗
PubMed2006

Adoptive transfer of CD4+ T cells reactive to modified low-density lipoprotein aggravates atherosclerosis.

OBJECTIVE: Atherosclerosis is associated with immune responses to oxidized low-density lipoprotein (oxLDL). The presence of activated macrophages and T cells in lesions suggests that cell-mediated immune reactions are taking place during the disease process. However, the role of specific immune responses has remained unclear. We have previously shown that transfer of CD4+ T cells from apolipoprotein E knockout mice (apoE(-/-)) into immunodeficient apoE(-/-) scid/scid mice accelerates disease. METHODS AND RESULTS: To test whether this effect is dependent on specific disease-associated antigens, purified CD4+ T cells from oxLDL-immunized mice were transferred into apoE(-/-) scid/scid mice. CD4+ T cells from mice immunized with a nonrelevant antigen, keyhole limpet hemocyanin (KLH), and naïve CD4+ T cells were used as controls. After 12 weeks, all mice that received T cells had larger lesions than untouched apoE(-/-) scid/scid controls. However, mice receiving CD4+ T cells from oxLDL immunized mice had substantially accelerated lesion progression compared with those receiving naive or KLH-primed T cells. Circulating levels of interferon-gamma were increased in proportion to the acceleration of atherosclerosis. CONCLUSIONS: These data show that adoptive transfer of purified CD4+ T cells from oxLDL-immunized mice accelerates atherosclerosis. They support the notion that Th1 cellular immunity is proatherogenic and identify oxLDL as a culprit autoantigen.

Adjuvants, Immunologic↗
PubMed2005

IL-18 binding protein fusion construct delays the development of diabetes in adoptive transfer and cyclophosphamide-induced diabetes in NOD mouse.

IL-18 is a type 1 pro-inflammatory cytokine with structural similarities to IL-1 and in synergy with IL-12 stimulates IFN-gamma production from T lymphocytes and polarizes development and function of Th1 cells. Because IL-1, IFN-gamma, and up-regulated Th1-mediated events are involved in the pathogenesis of both human and rodent type 1 diabetes mellitus, we have evaluated the effects of a specific inhibitor of IL-18 (the IL-18bp:FcIg) on the development of accelerated forms of autoimmune diabetes in NOD mice. The data show that prolonged prophylactic treatment with IL-18bp:FcIg significantly reduced the cumulative incidence of diabetes induced in NOD mice either by adoptive transfer of diabetogenic cells or by injection with large doses of cyclophosphamide. These data provide the first in vivo evidence for the diabetogenic role of IL-18 in immuno-inflammatory diabetogenic pathways in NOD mice.

Adoptive Transfer↗
PubMed1999

Cutting edge: chronic intestinal inflammation in STAT-4 transgenic mice: characterization of disease and adoptive transfer by TNF- plus IFN-gamma-producing CD4+ T cells that respond to bacterial antigens.

We generated transgenic mice for STAT-4, a regulatory protein specifically associated with IL-12 signaling, under the control of a CMV promoter. These mice expressed strikingly increased nuclear STAT-4 levels in lamina propria CD4+ T lymphocytes upon systemic administration of dinitrophenyl-keyhole limpet hemocyanin and developed chronic transmural colitis characterized by infiltrates of mainly CD4+ T lymphocytes. The latter cells produced predominantly TNF and IFN-gamma but not IL-4 upon activation with alphaCD3/CD28 or autologous bacterial Ags, consistent with a Th1-type cell response. Furthermore, chronic colitis in STAT-4 transgenic mice could be adoptively transferred to SCID mice by colonic and splenic CD4+ T cells that were activated with Ags from autologous bacterial flora. These data establish a critical molecular signaling pathway involving STAT-4 for the pathogenesis of chronic intestinal inflammation, and targeting of this pathway may be relevant for the treatment of colitis in humans.

Adoptive Transfer↗
PubMed1997

Tumor site-selective localization of an adoptively transferred T cell line expressing a macrophage lectin.

CTLL-2 cells were transfected with an expression vector that contained cDNA of a mouse macrophage galactose/N-acetylgalactosamine-specific calcium-type lectin (MMGL) and a stable transfectant (CTL-ML) was established. These cells and mock transfectant cells (CTL-CEP) were labeled with a long-term fluorescent cell tracer, DiI. The labeled cells were intravenously injected into mice that contained established lung metastases produced by OV2944-HM-1 ovarian tumor cells. Analyses with fluorescence microscopy of a series of frozen lung sections from the recipient mice revealed that CTL-ML preferentially accumulated in the lung metastatic nodules, whereas CTL-CEP did not. Time course studies showed that the preferential accumulation was evident 3 days after adoptive transfer. We also found that OV2944-HM-1 cells bound peanut agglutinin and Vicia villosa agglutinin B4, whose sugar specificity overlaps with the specificity of MMGL. These results suggested that MMGL molecules expressed on CTLL-2 cells contributed to their selective trafficking or retention in tumor foci possibly through recognition of tumor-associated cell surface carbohydrate antigens. These results also suggested that MMGL could be used for the selective targeting of effector cells in adoptive immunotherapy.

Adoptive Transfer↗
PubMed2002

Adoptive transfer of T cells induces airway hyperresponsiveness independently of airway eosinophilia but in a signal transducer and activator of transcription 6-dependent manner.

BACKGROUND: Activated T cells, through the release of specific cytokines (ie, IL-4, IL-5, and IL-13), regulate effector cell recruitment and function. In this way T cells orchestrate the inflammatory response, which leads to airway hyperresponsiveness (AHR), a cardinal feature of allergic asthma. OBJECTIVE: In the present study the direct role of T cells and, in particular, the importance of signal transducer and activator of transcription 6 (STAT6) in T cells was investigated in the development of AHR. METHODS: In a murine model of allergen-driven AHR, the effects of adoptive transfer of STAT6-containing (STAT6+/+) and STAT6-deficient (STAT6-/-) T cells from sensitized mice into allergen-challenged mice were tested. RESULTS: Although greater in STAT6+/+ mice, both allergen-challenged STAT6+/+ and STAT6-/- mice had AHR after transfer of T cells from sensitized STAT6+/+ mice. In contrast, AHR did not develop in allergen-challenged STAT6-/- mice after transfer of T cells from sensitized STAT6-/- mice. Reconstitution of AHR after T-cell transfer was not associated with airway eosinophilia. CONCLUSIONS: The data indicate that the STAT6 status of the donor mice is critical to the development of AHR. Although not critical for the development of AHR, the STAT6 status of the recipient mice might play a contributory-regulatory role in the AHR response. The results identify a STAT6-dependent T-cell pathway capable of modulating airway responsiveness, even in the absence of a significant airway eosinophilia.

Adoptive Transfer↗
PubMed2001

Adoptive transfer of a superantigen-induced hole in the repertoire of natural IgM-secreting cells.

We have recently evaluated the host response to the bacterial toxin, protein A from Staphylococcus aureus (SpA), which has the capacity to interact with B-cell antigen receptors encoded by V(H) clan III genes via a conserved variable region framework surface. In these studies, intraperitoneal instillation of SpA induced a persistent T-cell independent loss of a large supraclonal set of susceptible lymphocytes, which includes clan III/V(H) S107 family-expressing B-1 cells and their antibody products. To determine whether these long-term effects could represent the influence of residual in vivo deposited superantigen, we have now performed adoptive transfer of peritoneal B cells from superantigen- and control-treated donors. These studies demonstrated that mice that received cells from SpA-treated donors also exhibited the same induced supraclonal hole in the expressed repertoire of natural IgM-secreting cells due to supraclonal deletion. These studies clarify the cellular mechanisms responsible for B-cell superantigen-induced modification of the repertoires of in vivo polyclonal B-cell populations.

Adoptive Transfer↗
PubMed2000

Dendritic cells at a DNA vaccination site express the encoded influenza nucleoprotein and prime MHC class I-restricted cytolytic lymphocytes upon adoptive transfer.

Intradermal inoculation of plasmids expressing antigens that contain MHC class I-restricted epitopes leads to the induction of specific CD8(+) cytotoxic T lymphocytes (CTL). The role of in situ transfected antigen-presenting cells (APC) in the priming of specific CTL subsequent to intradermal DNA immunization was investigated using a plasmid (NPV1) expressing the nucleoprotein (NP) of influenza virus that contains a nuclear targeting signal and a dominant class I/K(d)-restricted epitope. Inoculation of NPV1 leads to in situ transfection of MHC class II(+) and class II(-) cells, as revealed by the nuclear localization of NP. Between 2 and 3% of MHC class II(+) and class II(-) cells with the ability to migrate out of the epidermis expressed NP. Upon adoptive transfer into naive recipients, class II(+) migratory cells recovered from the area inoculated with NP-expressing plasmid were significantly superior regarding the ability to prime virus-specific CTL as compared to MHC class II(-) cells. Together, these results are consistent with the role of local dendritic cells loaded with antigen in the priming of CTL by intradermal DNA immunization.

Adoptive Transfer↗
PubMed2000

Adoptive transfer of infectious bronchitis virus primed alphabeta T cells bearing CD8 antigen protects chicks from acute infection.

Infectious bronchitis virus (IBV) infection and associated illness may be dramatically modified by passive transfer of immune T lymphocytes. Lymphocytes collected 10 days postinfection were transferred to naive chicks before challenge with virus. As determined by respiratory illness and viral load, transfer of syngeneic immune T lymphocytes protected chicks from challenge infection, whereas no protection was observed in the chicks receiving the MHC compatible lymphocytes from uninfected chicks. Protection following administration of T lymphocytes could be observed in chicks with three distinct MHC haplotypes: B(8)/B(8), B(12)/B(12), and B(19)/B(19). Nearly complete elimination of viral infection and illness was observed in chicks receiving cells enriched in alphabeta lymphocytes. In contrast, removal of gammadelta T lymphocytes had only a small effect on their potential to protect chicks. The adoptive transfer of enriched CD8(+) or CD4(+) T lymphocytes indicated that protection was also a function primarily of CD8-bearing cells. These results indicated that alphabeta T lymphocytes bearing CD8(+) antigens are critical in protecting chicks from IBV infection.

Acute Disease↗