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PubMed1988

Immunity to coccidiosis: adoptive transfer in NIH mice challenged with Eimeria vermiformis.

The development of a reliable model for the adoptive transfer of immunity to coccidiosis (infection with Eimeria vermiformis in NIH mice) is described. More than 10(8) of a mixture of spleen and mesenteric lymph node (MLN) cells, given either intravenously or intraperitoneally, were required to transfer a significant degree of protection. Dividing cells, present in the donors at 10 or 14 days after priming, but not at 5 or 19 days, were shown to be the effectors. When examined separately, MLN cells were found to be superior to spleen cells, and the injection of as few as 5 x 10(7) was capable of substantially reducing the oocyst output from a challenge inoculum. The recipients of cells from primed mice had earlier, and sometimes higher, titres of specific antibodies in the serum but, overall, there was no correlation between these titres and protection. Further characterization of the cells responsible for adoptively transferring immunity to this infection should now be possible.

Animals↗
PubMed2004

Perforin knockout mice, but not mice with MAIDS, show protection against experimental cytomegalovirus retinitis after adoptive transfer of immune cells with a functional perforin cytotoxic pathway.

Adoptive transfer studies were performed to test the hypothesis that the perforin cytotoxic pathway is more important than the Fas/FasL cytotoxic pathway in protection against experimental murine cytomegalovirus (MCMV) retinitis. Splenic immune cells from donor MCMV-immunized normal mice or gld mice deficient in Fas/FasL-mediated cytotoxicity significantly reduced the frequency and severity of MCMV retinitis following subretinal MCMV challenge when transferred into recipient PKO mice deficient in perforin-mediated cytotoxicity. In sharp contrast, splenic cells from donor MCMV-immunized PKO mice failed to provide protection against MCMV retinitis when transferred into recipient PKO mice. Protection was not achieved, however, in recipient mice with retrovirus-induced immunodeficiency (MAIDS), even when splenic cells originated from MCMV-immunized normal mice.

Adoptive Transfer↗
PubMed2001

Manipulation of avidity to improve effectiveness of adoptively transferred CD8(+) T cells for melanoma immunotherapy in human MHC class I-transgenic mice.

The adoptive transfer of tumor-reactive CD8(+) T cells into tumor-bearing hosts provides an attractive alternative to vaccination-based active immunotherapy of melanoma. The development of techniques that result in the preferential expansion of tumor-reactive T cells is therefore of great importance. In this study, we report the generation of HLA-A*0201-restricted CD8(+) T cell populations that recognize either tyrosinase(369-376) or gp100(209-217) from tolerant human class I MHC-transgenic mice by using single amino acid-substituted variant peptides. Low peptide concentration or restimulation with the parent peptide was used to enhance the functional avidity, defined by stimulation of IFN-gamma accumulation, and cross-reactivity of the resulting T cell populations. We found a direct correlation between the ability of a T cell population to respond in vitro to low concentrations of the precise peptide expressed on the tumor and its ability to delay the outgrowth of B16 melanoma after adoptive transfer. Surprisingly, we found that some T cells that exhibited high functional avidity and were effective in controlling tumor outgrowth exhibited low structural avidity, as judged by MHC-tetramer staining. Our results establish strategies for the development and selection of CD8(+) T cell populations that persist despite peripheral tolerance, and that can control melanoma outgrowth. Furthermore, they support the use of human MHC class I-transgenic mice as a preclinical model for developing effective immunotherapies that can be rapidly extended into therapeutic settings.

Animals↗
PubMed1991

Use of adoptive transfer of tumor-infiltrating lymphocytes alone or in combination with cisplatin-containing chemotherapy in patients with epithelial ovarian cancer.

Lymphocytes isolated from fresh human epithelial ovarian tumors can be expanded in the presence of recombinant interleukin-2, and some CD8 antigen-positive lymphocytes can lyse autologous fresh tumor cells. We treated 7 patients with advanced or recurrent epithelial ovarian cancers, using the adoptive transfer of these tumor-infiltrating lymphocytes (TILs) following a single i.v. injection of cyclophosphamide. One case of disappearance (complete response) and 4 cases of greater than 50% decrease of tumor (partial response) were reported (14.3 and 57.1%, respectively). Regression of tumors in the ovary, liver, lung, and lymph node, both primaries and metastases, lasted for 3-5 months. Furthermore, 10 patients were treated alternately with a cisplatin-containing chemotherapeutic regimen and the adoptive transfer of TILs. Seven cases of complete regression and 2 cases of partial regression of cancer were reported. Four of the 7 patients with a complete response have had no recurrence for greater than 15 months of follow-up. It appears that this experimental technique of adoptive transfer of TILs achieves high response rates even without recombinant interleukin-2 administration and that the prospect of combined therapy using TILs and cisplatin offers hope for increasing the cure rate and long-term survival.

Adult↗
PubMed1988

Metabolic time course and immunologic concomitants of adoptive transfer of type I diabetes in the BB rat.

The metabolic and cellular immune changes during adoptive transfer of type I diabetes mellitus in the BB rat were examined. Concanavalin A (Sigma Chemical Co, St Louis) stimulation of acutely diabetic BB rat splenocytes increased the Ia-positive cells, but no other lymphocyte subset. Each spleen cell preparation was divided into two and injected into two separate recipients. Thirty-day-old diabetes-prone BB rats received these splenocytes intravenously (62 +/- 5 x 10(6) cells, n = 30) or buffer alone (controls, n = 14). Seventy-seven percent of the cell-injected rats became diabetic before 60 days of age, 15 +/- 1 days after injection. They were glucose intolerant two to three days before onset, with normal fasting glucose. All controls maintained normal glucose tolerance. The morphology revealed intense insulitis in all the rats that became diabetic, and its absence in all the controls. Eighty-three percent of the spleen cell preparations produced the same outcome in both recipients. The cell-injected rats had an increase in lymphocyte counts eight days after injection compared with the controls. The most affected subsets were the pan T cells (OX19+) and helper T cells (W3/25+). While the rats that ultimately became diabetic had a decrease of their lymphocyte subsets to control levels between eight and 14 days, the injected rats that maintained normal glucose tolerance maintained elevated T cells. We conclude that (1) adoptive transfer of diabetes occurs in the presence of an increase of the helper T (W3/25+) lymphocytes after spleen cell injections; (2) glucose intolerance precedes by two to three days fasting hyperglycemia; and (3) while the lymphocyte counts are increased in all recipients of splenocyte preparations, these counts decrease rapidly only in the rats that develop diabetes, possibly by entrapment of lymphocytes in the insulitis.

Animals↗
PubMed1996

Polyclonal expansion of adoptively transferred CD4+ alpha beta T cells in the colonic lamina propria of scid mice with colitis.

The adoptive transfer of low numbers of peripheral, non-fractionated CD4+ alpha beta T cells into histocompatible, severely immunodeficient (scid) hosts induces a colitis. This disease developed in C.B-17 scid/scid hosts after the injection of 10(5) CD4+ T cells purified from different peripheral lymphoid organs of immunocompetent C.B.-17 +/+ or BALB/cdm2 donor mice. Irrespective of their tissue origin, transferred CD4+ T cells selectively repopulated the scid host with gut-seeking CD4+ T cells. A chronic inflammatory bowel disease (IBD) developed as polyclonal populations of mucosa-seeking memory/effector CD4+ T cells accumulated in the gut lamina propria and epithelial layer of the adoptive host. The manifestation of colitis in the scid host correlated with the in situ polyclonal activation and expansion of adoptively transferred CD4+ T cells in the colonic lamina propria. Attempts were unsuccessful to select in vivo an oligoclonal CD4+ T cell population with an enhanced IBD-inducing potential by repeatedly reinjecting 10(5) donor-type CD4+ T cells from the colonic lamina propria of transplanted scid mice with an early and severe IBD into new scid hosts. The data indicate that the preferential repopulation of gut-associated lymphoid tissues with immunocompetent CD4+ T cells, and their polyclonal activation and in situ expansion in the lamina propria of the histocompatible, immunodeficient host are critical events in the pathogenesis of an IBD in this model.

Animals↗
PubMed2005

Adoptive transfer of dendritic cells modulates immunogenesis and tolerogenesis in a neonatal model of murine cutaneous leishmaniasis.

We evaluated the adoptive transfer of DCs on Leishmania (L.) mexicana-infected neonatal BALB/c mice. DCs were isolated and purified from the spleens of the following donor groups: a) Adult BALB/c mice infected during adulthood with L. (L) mexicana; b) Adult BALB/c mice infected during neonatal life; c) Healthy neonatal BALB/c mice; d) Healthy adult BALB/c mice. A neonatal model of infection, generated after inoculation with 5 × 105 promastigotes of L. (L) mexicana, was used as the infection control group. Sixteen hours after intraperitoneal transfer of DCs (1 × 103, 1 × 105, or 1 × 106 cells/ml), neonatal recipient BALB/c mice were infected. The adoptive transfer of DCs diminished disease progression in neonatal mice. This reduction depends on the quantity and provenance of transferred DCs, since the effect was more evident with high numbers of DCs from adult mice infected during adulthood and healthy neonatal mice. Protection was significantly reduced in animals receiving DCs from healthy adult mice but it was absent in mice receiving DCs from adult mice infected during neonatal life. These results suggest that genetic susceptibility to Leishmania infection can be modified during neonatal life, and that the period of life when antigens are encountered is crucial in influencing the capacity of DCs to induce resistance or tolerance.

Journal Article↗
PubMed1984

Cell-mediated immunity in experimental murine dermatophytosis. II. Adoptive transfer of immunity to dermatophyte infection by lymphoid cells from donors with acute or chronic infections.

An in vivo adoptive cell transfer system was used to investigate protective immunity during experimental murine dermatophytosis due to Trichophyton quinckeanum. Using sublethally (550R) irradiated BALB/c mice which are particularly susceptible to infection, it was found that regional lymph node cells from syngeneic acutely-infected donors conferred protection to irradiated recipients. By contrast, serum from the same donors did not prevent infection of normal BALB/c mice. The capacity of lymphoid cells to transfer adoptive immunity was lost after treatment with monoclonal anti-Thy-1.2 antibody and complement, but not after treatment with monoclonal anti-Ly 2.2 antibody and complement, indicating that cellular immunity is mediated by Ly 2-T cells. The cellular activity of chronically infected mice was also studied. Paradoxically, lymphoid cells from these animals which appeared to be immunologically compromised did, however, confer immunity. Adoptive immunity was abrogated by serum from chronically infected donors or by specific dermatophyte antigen, but not by homologous or heterologous anti-dermatophyte antiserum. These findings indicate that competition between cell-mediated immunity and humoral factors may be the causative mechanism for persistence of dermatophyte infection in this system.

Acute Disease↗
PubMedDate not supplied

Potassium Channel Blockers Inhibit Adoptive Transfer of Experimental Allergic Encephalomyelitis by Myelin-Basic-Protein-Stimulated Rat T Lymphocytes.

Agents which block T cell K(+) currents can prohibit both proliferative and effector cell functions in T cells activated by mitogens or phorbol esters. This study examined the effects of some of these blocking agents on the immune responsiveness of guinea pig myelin basic protein (GPMBP)-reactive Lewis rat T lymphocytes, which are capable of mediating the adoptive transfer of experimental allergic encephalomyelitis (EAE), an accepted animal model for multiple sclerosis. Both the proliferative functions (DNA synthesis and cell blastogenesis) and the EAE transfer activities of GPMBP-reactive lymphocytes were examined following GPMBP-induced activation in the presence of agents shown to block the outwardly rectifying K(+) current in these cells. At concentrations which completely inhibited DNA synthesis, as measured by [(3)H]thymidine incorporation, and cell blastogenesis, tetraethylammonium (TEA), 4-aminopyridine (4-AP) and methoxyverapamil (D60) completely blocked the subsequent adoptive transfer of EAE into naive syngeneic Lewis rats. The concentrations at which these blockers produced a 50% reduction in DNA synthesis were estimated to be 16, 1.6 and 32 &mgr;M for TEA, 4-AP and D-600, respectively, which were roughly equivalent to the EC(50) to block the K(+) current. Apamine, a potent Ca(2+)-activated K(+) channel blocker, at a concentration several orders of magnitude higher than is necessary to block Ca(2+)-activated K(+) channels, reduced the maximal K(+) conductance in GPMBP-reactive T cell K(+) channels by about 20%, but did not alter either [H(3)H]thymidine incorporation or the adoptive transfer of EAE. These results indicate that delayed rectifier K(+) channel blockers may prevent the activation of GPMBP-reactive T cells, thus prohibiting encephalitogenic effector cell functions. Copyright 1997 S. Karger AG, Basel

Journal Article↗
PubMed1983

Autoimmune effector cells. V.A monoclonal antibody specific for rat helper T lymphocytes inhibits adoptive transfer of autoimmune encephalomyelitis.

The in vitro activation of spleen cells from donor rats immunized with myelin basic protein results in enhanced adoptive transfer of experimental allergic encephalomyelitis to syngeneic recipients. In this study, adoptive transfer was inhibited when monoclonal antibody W3/25, which defines an antigen on rat helper T lymphocytes, was included in the in vitro cultures. Partial inhibition was achieved with monoclonal antibody OX-3, which recognizes la antigen, whereas other anti-T cell monoclonal reagents were ineffective. These results support the conclusion that W3/25+T cells play an essential role in the induction of this autoimmune response.

Animals↗
PubMed1999

An adoptive transfer model of allergic lung inflammation in mice is mediated by CD4+CD62LlowCD25+ T cells.

Animal models of allergic lung inflammation have provided important insight into the cellular and biochemical factors involved in the pathogenesis of human asthma. Herein, we describe an adoptive transfer model of OVA-specific eosinophilic lung inflammation in the mouse that is used to characterize the cells involved in mediating the pulmonary inflammatory response. We report that freshly isolated spleen cells from OVA-sensitized mice are unable to prime naive recipient mice to respond to a subsequent OVA aerosol challenge. Subjecting the spleen cells to short term restimulation with Ag in vitro, however, renders the cells competent to transfer activity. The magnitude and the kinetics of the eosinophilic pulmonary inflammation in the adoptive transfer recipients are nearly identical with those generated by a more conventional active sensitization/challenge protocol, with the notable exception of differential production of plasma IgE in the two models. Extensive negative and positive selection of splenocyte subtypes indicates that the transfer of Ag-primed CD4+ T cells is both necessary and sufficient to establish full responsiveness in the recipient mice. Additional phenotypic characterization of the transfer-reactive CD4+ T cells indicates that they are found within the CD62LlowCD25+ subset and secrete high levels of IL-5 in response to Ag stimulation. Limiting dilution analysis-derived minimal frequency estimates indicate that approximately 1 in 8500 of the sensitized, cultured spleen cells produces IL-5 in response to OVA stimulation in vitro, suggesting that eosinophilic lung inflammation can be induced in naive mice by the transfer of <1200 Ag-specific CD4+ T cells.

Administration, Inhalation↗
PubMed1999

MHC-restricted protection of cats against FIV infection by adoptive transfer of immune cells from FIV-vaccinated donors.

The role of cellular immunity in vaccine protection against FIV infection was evaluated using adoptive cell transfer studies. Specific-pathogen-free cats received two adoptive transfers of washed blood cells from either vaccinated or unvaccinated donors with varying MHC compatibility at 1-week intervals, and a homologous FIV(Pet) challenge 1 day after the first adoptive transfer. FIV-specific CTL, IFN-gamma production, and proliferation responses were detected in the PBMC from the vaccinated donors. Seven of eleven (64%) recipients of cells from half-matched/vaccinated donors remained negative for FIV-antibodies after FIV challenge and four of those were completely protected. Two of two recipients of cells from MHC-identical/vaccinated donors were completely protected. All recipients of cells from unrelated/vaccinated, half-matched/unvaccinated, or unrelated/unvaccinated donors were unprotected. Thus, protection mediated by adoptive transfer of immunocytes from vaccinated cats was MHC-restricted, occurred in the absence of antiviral humoral immunity, and correlated with the transfer of cells with FIV-specific CTL and T-helper activities.

Adoptive Transfer↗
PubMed1987

Characterization of a cell population in thoracic duct lymph that adoptively transfers rejection of adult Trichinella spiralis to normal rats.

In Trichinella spiralis-infected rats, a population of cells in thoracic duct lymph (TDL) that can adoptively transfer protection to naive rats was identified and characterized. During the course of T. spiralis infection, blast cells appeared in lymph from Day 3-4, and only Day 3-4 TDL cells had protective properties after transfer. Protection was evident in a 1-2-day increase in the slow rejection of adult worms beginning 8-9 days after the challenge infection. The minimum number of TDL cells capable of transferring protection was 1.8 X 10(8) cells. Transferred cells could protect against a challenge infection with adult worms alone. A double cross-over experiment demonstrated that major histocompatibility complex identity was essential for effective transfer of protection (MHC restriction). An experiment using the mitotic inhibitor vinblastine showed that the protective cells belonged to a dividing cell population. The phenotype of the protective TDL was confirmed by a two-step cell separation procedure. First, it was demonstrated that surface Ig- cells (T cells) separated by affinity chromatography could transfer protection. Second, these surface Ig- cells were divided into two subpopulations by panning using monoclonal antibodies OX-8 and W3/25. The results showed that W3/25+ or OX-8- cells (T-helper) were effective in transferring protection. Protection was only seen when rats adoptively transferred with cells were challenged 1 day after cell transfer.

Animals↗
PubMed1992

Adoptive transfer of bryostatin 1-activated T cells provides long-term protection from tumour metastases.

Treatment of human cancer with tumour-specific T lymphocytes is limited by the frequent unavailability of autologous tumour to stimulate T-cell growth and by the toxicity associated with high-dose interleukin-2 (IL-2) treatment. In the present study we demonstrate that Bryostatin 1 (B) plus ionomycin (I) can substitute for tumour antigen and activate tumour-bearing hosts' T-cells which provide long-term protection against tumour challenge after adoptive transfer. Lymphocytes obtained from the popliteal lymph nodes (DLN) draining an MCA-105 footpad sarcoma were stimulated with B/I, and then cultured for 7 days with 20 U ml-1 IL-2. This in vitro stimulation protocol consistently expanded cell numbers greater than 20-fold during 7 days. Mice given B/I-stimulated draining lymph node (DLN) cells were protected from specific i.v. tumour challenge for at least 15 weeks after adoptive transfer, even in the absence of IL-2 treatment. Tumour immunity conferred by B/I-activated DLN cells was systemic and independent of host T-cells. However, resistance to tumour challenge was lost when either CD4+ or CD8+ T-cells were depleted in vivo. These studies indicate that DLN cells activated with bryostatin 1 and ionomycin persist long-term in vivo as functional memory cells after adoptive transfer.

Adjuvants, Immunologic↗
PubMedDate not supplied

Adoptive transfer of anti-idiotypic T cells cure mice of disseminated B cell lymphoma.

There is extensive interest in idiotypic vaccination as a treatment of lymphoma. An alternative approach is the adoptive transfer of in vitro generated T cells. This strategy has been used to treat posttransplantation EBV-related diseases. The ability to generate in vitro T cells to peptides derived from immunoglobulin idiotypes raises the possibility of directly using such cells as a treatment of lymphoma. Investigating the adoptive transfer of specific T cells to idiotype derived peptides in a murine lymphoma model is therefore an important part of the clinical translation of this alternative approach. We have generated an idiotype-specific T cell line, able to recognise a defined, naturally processed idiotype-derived epitope. This line has been used to successfully treat mice with disseminated lymphoma supporting the clinical use of idiotype specific T cells.

Adenoviridae↗
PubMed1987

Synergistic effects of the xid gene in X chromosome congenic mice. I. Inability of C3.CBA/N mice to respond to thymus-dependent antigens in adoptive transfer assays.

The xid gene, which causes a B lymphocyte immune defect in CBA/N mice, has been bred onto the C3H/HeN background. The resulting X chromosome congenic mice (C3.CBA/N) exhibit immunologic defects that are much more profound than the defect exhibited by CBA/N mice; thus, the B cells from C3.CBA/N mice not only fail to respond to thymus-independent (TI) type 2 antigens such as TNP-Ficoll, but they fail to respond in vitro to TI-type 1 antigens such as TNP-Brucella abortus (BA) and B cell mitogens such as LPS and Nocardia water-soluble mitogen. In this paper we show that the synergistic defect seen in C3.CBA/N B cells is also elicited in adoptive transfer assays to thymus-dependent (TD) antigens such as TNP-KLH and PC-KLH, antigens to which both parental strains respond. Thus, the secondary adoptive transfer response of C3.CBA/N spleen cells is generally less than 5% of the immune response produced by CBA/N or C3H/HeN spleen cells. This synergistic defect is restricted to the C3.CBA/N B cells, since C3.CBA/N T cells can provide help to CBA/N B cells that is equivalent to the help obtained with CBA/N T cells. The low responsiveness of C3.CBA/N spleen cells to TD antigens, which is elicited in adoptive transfer assays, is not seen when the intact animal is immunized with antigen in CFA; this, intact C3.CBA/N mice produce anti-PC-KLH and anti-TNP-KLH responses only slightly lower than the responses of CBA/N mice to these same antigens. In contrast, when these mice are immunized with phenol-extracted LPS, a TI-type 1 antigen, their antibody responses are severely depressed. These data suggest that under conditions in which T cell help may be limiting or in which the intact physiology of the T and B cells has been disrupted, C3.CBA/N B cells demonstrate profound immunologic impairment; however, when adequate T cell help is available and the splenic architecture is not disrupted, their immune responses appear to progress in a normal fashion.

Animals↗
PubMed1997

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↗
PubMed1995

Prolonged disease-free period in patients with advanced epithelial ovarian cancer after adoptive transfer of tumor-infiltrating lymphocytes.

Thirteen patients with epithelial ovarian cancer, who did not show any detectable lesion after cisplatin-containing chemotherapy following primary operation, were treated with adoptive transfer of tumor-infiltrating lymphocytes (TIL group). Eleven patients with almost equivalent conditions of disease, who were treated with only chemotherapy following primary operation, served as a control group. The median time of follow-up was 36 (range, 23-44) months in the TIL group and 33 (range, 14-48) months in the control group. The estimated 3-year overall survival rate of disease-free patients in the TIL group and in the control group was 100% and 67.5%, respectively. A significant difference was noticed between the overall survival rate of the TIL group and the control group (P < 0.01). Furthermore, the estimated 3-year disease-free survival rate of the patients in the TIL group and in the control group was 82.1% and 54.5%, respectively. The disease-free survival rate of patients in the TIL group and in the control group was significantly different (P < 0.05). These results suggest that the adoptive transfer of TILs after all chemotherapy has been finished might be one promising method to achieve complete cure of advanced epithelial ovarian cancer.

Adenocarcinoma↗