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PubMed1987

Therapy of cancer using the adoptive transfer of activated killer cells and interleukin-2.

A new approach to cancer treatment has been developed based on the adoptive transfer of activated lymphocytes into cancer patients. Lymphocytes harvested from patients by leukapheresis are converted into lymphokine-activated killer (LAK) cells by incubation with recombinant interleukin-2 (rIL-2). These LAK cells are then infused back into the patients in combination with intravenous IL-2. Among 25 patients treated with this form of adoptive immunotherapy there were 11 patients with measurable tumor reductions, including 1 complete responder. The majority of responses occurred in patients with metastatic renal cell carcinoma, melanoma and colorectal carcinoma. The toxicities of IL-2, including fluid retention and pulmonary edema, limit therapy, and laboratory investigation is now aimed toward understanding the mechanism of IL-2 toxicity. The use of LAK cells and IL-2 in cancer therapy is still in a developmental stage and needs to be refined before its role can be definitely established.

Clinical Trials as Topic↗
PubMedDate not supplied

Accumulation of adoptively transferred A-NK cells in murine metastases: kinetics and role of interleukin-2.

Infiltration of lung metastases by adoptively transferred A-NK cells was time- and dose-dependent. Infiltration became significant 6 hours after injection and reached a maximum after 16-24 hours. When no exogenous IL-2 was administered to support the injected cells, hardly any A-NK cells infiltrated the tumors. More A-NK cells accumulated in the tumors when high doses of IL-2 were given compared to lower doses. Significantly more A-NK cells accumulated in the tumours when the total dose of IL-2 was given as many small doses at short intervals compared to larger doses given less frequently. Use of IL-2 complexed to Polyethylene-glycol (Peg-IL-2) resulted in a significantly better tumor infiltration by A-NK cells than use of regular IL-2. IL-2 administered in mini-osmotic pumps did not lead to a better infiltration than ip injections of the same amount of IL-2. The route of administration of IL-2 did not seem to influence the degree of infiltration.

Animals↗
PubMed1990

[Immunogenetic analysis of delayed hypersensitivity to tuberculin in mice by the method of local adoptive transfer].

It has been demonstrated that a specific phase of DTH reaction to tuberculin is carried out (and in adoptive transfer-transferred) by T-lymphocytes with Lyt-1+, Lyt-2-, L3T4+ phenotype by a method of local adoptive transfer of this reaction from BCG-immunized mice to the pads of intact recipients. From genetic viewpoint, the above reaction is limited by 1-A beta, 1-A alpha genes. In a syngeneic apposition, monoclonal antibodies anti-1-A kappa beta (without complement) were blocking the reaction transfer to CBA mice A beta chain affected mutation bm12 failed to limit the reaction transfer in apposition B6----B6.C-H-2bm12.

Animals↗
PubMed2000

Adoptive transfer of immunity with intraepithelial lymphocytes in Cryptosporidium parvum-infected severe combined immunodeficient mice.

BACKGROUND: Intestinal infections with the protozoan parasite Cryptosporidium parvum are prevalent in both immunocompetent and immunocompromised hosts. Although C parvum is an important cause of outbreaks and opportunistic infections worldwide, little is known about protective mucosal immune responses. This is in part because animal models of infection are limited to those with genetic or induced immunodeficiencies. METHOD: In this report, we isolated immune (primed) or nonimmune (unprimed) intraepithelial lymphocytes (IEL) from BALB/cJ mouse intestines, adoptively transferred them into C parvum-infected severe combined immunodeficient (SCID) mice, and evaluated infection and cell phenotype responses. RESULTS: Control SCID mice that received no IEL shed large numbers of oocysts throughout the experimental period (day 18 to day 72). Transfer of primed IEL significantly reduced fecal oocyst shedding in recipient SCID mice compared with SCID mice that received unprimed IEL or no IEL. SCID mice transferred with unprimed IEL shed variable numbers of fecal oocysts that increased and decreased in bursts until day 57 after infection. SCID mice transferred with primed IEL exhibited significantly higher proportions of T-cell receptor (TCR) alphabeta+, CD8+, and CD8alphabeta+ EL compared with inoculated SCID mice that received unprimed or no IEL. CONCLUSION: We conclude that primed IEL from immunocompetent mice may influence protective mucosal response against cryptosporidiosis when transferred into SCID mice. In addition, the increased percentage of TCR alphabeta+, CD8+, CD8alphabeta+ IEL in recipient SCID mice may reflect mucosal cell populations involved in these responses during chronic C parvum infection.

Adoptive Transfer↗
PubMed2003

Adoptive transfer of islet antigen-autoreactive T cell clones to transgenic NOD.Ea(d)mice induces diabetes indicating a lack of I-E mediated protection against activated effector T cells.

Transgenic insertion of the MHC class II Ea(d)gene in NOD mice restores I-E expression and prevents T-cell-mediated autoimmune diabetes (IDDM). The specific molecular and cellular mechanisms responsible for the diabetes resistance of transgenic NOD.Ea(d)mice remain unclear. We adoptively transferred islet antigen-specific T cell clones into NOD and transgenic NOD.Ea(d)mice to evaluate the level of protection provided by I-E expression against activated effector T cells. We have found that neither neonatal or 3-5-week-old I-E-expressing NOD.Ea(d)mice can completely inhibit the diabetogenic activities of activated islet antigen-specific T cell clones. These data indicate that Ealpha protein expression in NOD antigen presenting cells (APC) does not reduce islet autoantigen presentation in the context of I-A(g7)below the threshold required for stimulation of effector/memory diabetogenic T cells. Our results suggest that the mechanism of Ealpha protein-mediated diabetes resistance in NOD mice may be "antigen ignorance," in which the quantity of islet autoantigens presented in the context of I-A(g7)by APC is reduced below the threshold required to activate nai;ve islet antigen-specific T cells.

Adoptive Transfer↗
PubMed2004

Immunoglobulin treatment suppressed adoptively transferred autoimmune myocarditis in severe combined immunodeficient mice.

We investigated the suppressive effects of immunoglobulin (Ig) on effector T cells in autoimmune myocarditis. Treatment with Ig reduced production of the so-called T-helper type 1 (Th1) cytokines stimulated by concanavalin A or cardiac myosin in cultured lymph node (LN) cells from rats with myocarditis. The cytotoxic activities of LN cells from rats immunized with myosin and treated with Ig were reduced against cardiomyocytes and F-2 cells compared with those treated without Ig. The adoptive transfer of myocarditis from LN cells of Lewis rats with myocarditis to severe combined immunodeficient (SCID) recipients was successfully achieved. Treatment with Ig, but not with F(ab')2 fragments of Ig, reduced the mortality and severity of myocarditis in SCID recipient mice. Decreased ability of LN cells of Ig-treated rats, but not rats treated with F(ab')2 fragments, to transfer autoimmune myocarditis was also demonstrated. The findings of the present study suggest that autoimmune myocarditis was successfully transferred to SCID mice and that treatment with Ig ameliorated autoimmune myocarditis by inducing selective myosin unresponsiveness via the Fc portion, resulting in suppression of Th1 cytokine production and cytotoxic activities of LN cells, which operated together in the development of autoimmune myocarditis.

Adoptive Transfer↗
PubMed1984

Babesia microti in mice. Subpopulations of cells involved in the adoptive transfer of immunity with immune spleen cells.

Protection against a primary Babesia microti infection in mice, induced by the adoptive transfer of immune spleen cells, was abolished when the immune spleen cells were treated with mitomycin C prior to transfer. Since mitomycin C treatment prevents the replication of lymphocytes without affecting other cell functions, these results would suggest that the transferred cells required proliferation in the recipient mice before they could exert their protective effect, and this excludes the already differentiated antibody-forming cells (AFC's), macrophages and sensitised helper T cells. This was partly supported by the finding that Sephadex G-10 non-adherent immune cells, depleted of macrophages and AFC's, still conferred a strong protection after transfer. However, the Sephadex G-10 adherent cells, on a cell to cell basis, initially conferred a better protection against B. microti than did the non-adherent cells or unfractionated immune spleen cells. The possibility of the retention of an intermediate B memory cell type on the Sephadex G-10 columns and the suppression of antibody production are discussed in view of these results.

Animals↗
PubMed1996

In vivo trafficking of adoptively transferred interleukin-2 expanded tumor-infiltrating lymphocytes and peripheral blood lymphocytes. Results of a double gene marking trial.

Adoptive immunotherapy with tumor-infiltrating lymphocytes (TIL) and IL-2 appears to produce dramatic regressions in patients with metastatic melanoma and renal cancer. However, the in vivo mechanism of TIL function is not known. We conducted an UCLA Human Subject Protection Committee, Recombinant DNA Advisory Committee, and FDA-approved clinical trial using genetically-marked TIL to test the hypothesis that these cells have unique, tumor-specific in vivo trafficking patterns. TIL and PBL (as a control effector cell population) were isolated and expanded in parallel in vitro in IL-2-containing medium for 4-6 wk. During the expansion, TIL and PBL were separately transduced with the amphotropic retroviral vectors LNL6 and G1Na. Transduced TIL and PBL were coinfused into patients and their respective numbers measured in tumor, peripheral blood, and normal tissues; integrated provirus could be quantitated and distinguished by DNA PCR. Nine patients were treated (six melanoma, three renal) and received between 4.5 x 10(8) and 1.24 x 10(10) total cells. Both "marked" TIL and PBL could be detected circulating in the peripheral blood, in some patients for up to 99 d after infusion. Marked TIL and/or PBL could be detected in tumor biopsies in six of nine patients as early as day 6 and as late as day 99 after infusion. No convincing pattern of preferential trafficking of TIL vs. PBL to tumor was noted. Moreover, concurrent biopsies of muscle, fat, and skin demonstrated the presence of TIL/PBL in comparable or greater numbers than in tumor in five patients. The results of this double gene marking trial provide interesting insights into the life span and trafficking of adoptively transferred lymphocytes, but do not support the hypothesis that TIL specifically traffic to tumor deposits.

Adult↗
PubMed2004

Adoptive transfer of paternal antigen-hyporesponsive T cells induces maternal tolerance to the allogeneic fetus in abortion-prone matings.

The embryo expresses paternal Ags foreign to the mother and therefore has been viewed as an allograft. It has been shown that anergic T cells generated by blocking of the CD28/B7 costimulatory pathway with anti B7-1 and anti B7-2 mAbs can be transferred as suppresser cells to prevent allograft rejection. Little is known, however, about the in vivo function of anti-B7-treated T cells after their transfer into abortion-prone mice in the maintenance of materno-fetal tolerance. In the present study, abortion-prone CBA/J females mated with DBA/2 males were administered anti-B7-1 and anti-B7-2 mAbs on day 4 of gestation (murine implantation window). The anti-B7-treated T cells subsequently were adoptively transferred into abortion-prone CBA/J mice. We demonstrated that costimulation blockade with anti-B7 mAbs at the time of implantation resulted in altered allogeneic T cell response and overcame increased maternal rejection to the fetus in the CBA/JxDBA/2 system. The transferred anti-B7-treated T cells appeared to be regulatory, decreasing responsiveness and generating clonal deviation in maternal recipient T cells. The transferred CFSE-labeled T cells were found to reside in the spleen and uterine draining lymph nodes, and a few were localized to the materno-fetal interface of the maternal recipient. Our findings suggest that the anti-B7-treated T cells not only function as potent suppresser cells, but also exert an immunoregulatory effect on the maternal recipient T cells, which cosuppresses maternal rejection to the fetus. This procedure might be considered potentially useful for fetal survival when used as an immunotherapy for human recurrent spontaneous abortion.

Abortion, Spontaneous↗
PubMed2004

D-penicillamine-induced autoimmunity in the Brown Norway rat: role for both T and non-T splenocytes in adoptive transfer of tolerance.

The D-penicillamine autoimmune syndrome observed in Brown Norway (BN) rats is similar to an idiosyncratic reaction seen in some patients. We have previously shown that 2 weeks of low dose (5 mg/day) D-penicillamine pretreatment completely prevented all clinical signs of autoimmunity normally observed in 60-80% of rats treated with high dose (20 mg/day) D-penicillamine. We demonstrated that this tolerance is immune-mediated; tolerance to D-penicillamine is long lasting, we can adoptively transfer splenocytes from tolerant rats into slightly irradiated naive syngeneic recipients, and rats exposed to low dose D-penicillamine produce tolerogenic cytokines [Masson, M. J., and Uetrecht, J. P. (2004) Tolerance induced by low dose D-penicillamine in the brown norway rat model of drug-induced autoimmunity is immune-mediated. Chem. Res. Toxicol. 17, 82-94]. The aim of this study was to provide further understanding of the cells that are responsible for transferring tolerance and to assess the presence of regulatory T cells in the spleen of tolerant animals. We cotransferred T cells or splenocytes depleted of T cells from tolerant BN rats with splenocytes from naive BN rats into lightly irradiated syngeneic recipients. We found that neither tolerant splenocyte subpopulation could completely prevent clinical signs of autoimmunity. These results demonstrate that immune tolerance to D-penicillamine-induced autoimmunity may require both antigen presenting cells and T cells.

Administration, Oral↗
PubMed2005

Neospora caninum: adoptive transfer of immune lymphocytes precipitates disease in BALB/c mice.

Neospora caninum is a recently described apicomplexan parasite first isolated from a dog in 1988 and has subsequently been shown to infect a wide range of mammals. In mice, Neospora can cause primary pneumonia, myositis, encephalitis, radiculoneuritis, and pancreatitis. Whereas, certain aspects of the host immune response to Toxoplasma gondii have been well studied, not as much is known about the full immune response to Neospora. This paper examines whether or not immune splenocytes are able to adoptively transfer protection against N. caninum infection in BALB/c mice. Mice receiving immune enriched CD8+ cells had severe neurological signs by 19 days post infection. Mice receiving immune enriched CD4+ cells had mild neurological signs on day 22 post infection. It would appear that additional immune cells can precipitate disease in the presence of circulating lymphocytes.

Adoptive Transfer↗
PubMed1998

Deletion of Plasmodium berghei-specific CD4+ T cells adoptively transferred into recipient mice after challenge with homologous parasite.

The immune response to malaria parasites includes T cell responses that reduce parasites by effector T cell responses and by providing help for antibody responses. Some parasites are more sensitive to antibody and others are more sensitive to cell-mediated immunity. We demonstrate that cultured CD4(+) T cells that produce interferon gamma and interleukin 2, but not interleukin 4, in response to stimulation with the rodent parasite Plasmodium berghei can reduce but not eliminate parasites in vivo after adoptive transfer. Although cells can persist in vivo for up to 9 months in uninfected mice, infection results in elimination of up to 99% of specific T cells in different tissues, as judged by tracking T cells labeled with the fluorescent dye 5-(and -6)-carboxyfluorescein diacetate succinimidyl ester. T cells specific for ovalbumin are unaffected. In vivo activation and division of transferred T cells per se are not responsible for deletion because T cells positive for 5-(and -6)-carboxyfluorescein diacetate succinimidyl ester divide up to six times within 7 days in uninfected mice and are not deleted. Understanding the factors responsible for parasite-mediated specific deletion of T cells would enhance our knowledge of parasite immunity.

Adoptive Transfer↗
PubMedDate not supplied

Suppression of myosin-induced and adoptively transferred myocarditis by prior treatment with complete Freund's adjuvant.

BACKGROUND: We evaluated the effect of pretreatment with complete Freund's adjuvant (CFA) on experimentally induced myocarditis concomitant with the assessment of antigen-specific properties of disease-triggering lymphocytes. METHODS AND RESULTS: Rats pretreated with CFA a week prior to myosin immunization developed a significantly attenuated myocardial inflammation as compared to control-treated animals. Furthermore, prior administration of CFA virtually abolished histological evidence of myocarditis induced by transfer of antimyosin lymphocytes. CFA administered subcutaneously prior to myosin immunization resulted in a significant reduction in lymph node cell reactivity to myosin. Assessment of cultured medium from lymphocytes obtained from CFA-pretreated myosin-immunized rats revealed reduced levels of interferon gamma but an increased production of IL-10, suggesting an induction of a Thl to Th2 switch. CONCLUSIONS: Thus, CFA treatment suppressed both myosin-induced as well as adoptively transferred myocarditis concomitant with induction of antigen-specific unresponsiveness to myosin and skewing of the immune response in favor of a Th2-dominated profile.

Adjuvants, Immunologic↗
PubMed1997

A simple method for evaluating the rejection of grafted spleen cells by flow cytometry and tracing adoptively transferred cells by light microscopy.

In this report we describe a simple method using the vital dye 5- (and 6-) carboxyfluorescein diacetate succinimidyl ester (CFSE) to follow splenic graft rejection by flow cytometry. CFSE-labelled spleen cell suspensions were injected intravenously into various recipients and blood samples were taken at different time points to follow the transferred cells. We found that the labelled cells could be readily detected by flow cytometry for up to eleven weeks. The loss of these labelled cells in various transfusion experiments with different major and minor histocompatibility differences followed the rejection kinetics previously described for skin transplants. Thus, this method offers a simple tool to test the histocompatibility of donor cells/grafts with the host in adoptive/transplantation experiments in which donor and host are not completely syngeneic. Furthermore, we developed a method to trace adoptively transferred fluorescent CFSE-labelled cells by light microscopy by converting in situ immunofluorescence staining into immunoenzyme staining.

Adoptive Transfer↗
PubMed1989

In vivo expression of perforin by CD8+ lymphocytes in autoimmune disease. Studies on spontaneous and adoptively transferred diabetes in nonobese diabetic mice.

A potent cytolytic pore-forming protein (perforin or cytolysin) has previously been found to be associated with the cytoplasmic granules of CTL and NK cells. Inasmuch as all previous studies on perforin have been conducted with cultured CTL and NK cell lines, it is not clear whether perforin may play a role in the cytotoxicity mediated by CTL that have been primed in vivo. In this study, we investigated the presence of perforin in pancreata from nonobese diabetic (NOD) mice, which have been studied as a model of autoimmune, insulin-dependent (type I) diabetes mellitus. Whereas adult NOD mice spontaneously develop diabetes, it is possible to induce diabetes in young, irradiated NOD mice by adoptive transfer of splenocytes obtained from diabetic donors. By means of immunohistochemical analysis, we were able to detect perforin Ag in a small subpopulation of CD8+/Thy-1+/asialo GM1-/CD4- lymphocytes in the pancreatic islets of animals undergoing both spontaneous and adoptive transfer-mediated insulitis. Perforin+/CD8+ lymphocytes were found in small clusters and were observed to display the morphology of large granular lymphocytes. These observations show for the first time the presence of perforin-containing CD8+ lymphocytes in tissues of animals undergoing autoimmune disease.

Animals↗
PubMed1999

Genetic dissection of SLE pathogenesis: adoptive transfer of Sle1 mediates the loss of tolerance by bone marrow-derived B cells.

Sle1 is a potent autoimmune susceptibility locus on chromosome 1 originally identified in a genome scan of testcross progeny between the systemic lupus erythematosus-prone NZM2410 strain and C57BL/6. We subsequently produced B6.NZMc1, a congenic strain carrying the NZM2410-derived Sle1 genomic interval on the B6 background and demonstrated that Sle1 mediated the loss of tolerance to chromatin in both the B and T cell compartments. In this communication, we show by adoptive transfer experiments that the autoimmune phenotypes of Sle1 are completely reconstituted in B6 radiation chimeras receiving B6.NZMc1 bone marrow but not by the reciprocal reconstitution, demonstrating that Sle1 is functionally expressed in B cells. In additional experiments, cotransfer of mixtures of bone marrow derived from B6.NZMc1 and nonautoimmune congenic B6 mice carrying allelic T and B cell markers showed that only B cells derived from B6.NZMc1 bone marrow produced anti-chromatin autoantibodies. In contrast, increased expression of CD69 was equivalent in CD4+ T cells derived from either B6.NZMc1 or congenic B6 bone marrow, suggesting that either T cell population could be activated subsequent to loss of tolerance in the B cell compartment. These findings indicate that the expression of Sle1 in B cells is essential for the development of autoimmunity.

Adoptive Transfer↗
PubMed1996

CD4+CD8- thymocytes that express L-selectin protect rats from diabetes upon adoptive transfer.

Previous studies have shown that insulin-dependent diabetes can be induced in normal PVG.RT1u rats by a protocol of adult thymectomy and irradiation. The injection of CD4+ T cells from non-irradiated syngeneic donors prevents the onset of disease in approximately 50% of pre-diabetic recipients but all rats are protected if a particular subset of CD4+ cells is transferred. These protective cells express TCR alpha beta and have a memory phenotype, being CD45RClow RT6+. Further studies have demonstrated that the transfer of CD4+CD8- thymocytes, like that of unfractionated CD4+ peripheral T cells, also protects approximately half of recipients from diabetes suggesting that, as with the peripheral T cells, a functional heterogeneity may exist amongst CD4+CD8- thymocytes. In this study, we show that L-selectin is expressed by 50-60% of all CD4+CD8- thymocytes from 6-week-old rats. Adoptive transfer of these populations into thymectomized and irradiated rats revealed that the protection from diabetes observed by CD4+CD8- thymocytes was mediated almost entirely by the L-selectin+ subset. Cells with this phenotype were also able to mediate both humoral and cell mediated responses, providing primed B cells with help for secondary antibody responses and mediating local graft-versus-host reactions. L-selectin- CD4+CD8- thymocytes failed to mediate these responses. These data indicate that CD4+CD8- thymocytes must mature to the stage of L-selectin expression, before they can mediate normal T cell function. The implications of these results are discussed with respect to the possible role of murine NK1.1+ thymocytes in the control of autoimmunity.

Adoptive Transfer↗
PubMed2005

The Helicobacter felis model of adoptive transfer gastritis.

The bacterium Helicobacter pylori is a major human pathogen and the principal cause of acute and chronic gastritis, gastric and duodenal ulcer disease, and gastric adenocarcinoma. Infection with gastric Helicobacter results in an early infiltration of neutrophils, monocytes, and natural killer cells, followed by an influx of T cells and plasma cells. Although the critical components of this gastric infiltrate that lead to disease are unclear, the Helicobacter felis-infected mouse and other mouse models of Helicobacter-associated gastritis have demonstrated the critical nature of adaptive immunity in the development of gastric epithelial pathology. To further investigate the role of adaptive immunity in this disease, adoptive transfer models of disease have also been utilized. These models clearly demonstrate that it is the host CD4+ T lymphocyte response that is crucial for the development of Helicobacter-associated gastric epithelial changes.

Adoptive Transfer↗