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PubMed1980

Protection of mice from lethal flaviviral encephalitis by adoptive transfer of splenic cells from donors infected with live virus.

C3H/RV mice, which are genetically resistant to lethal flaviviral infection were susceptible to lethal challenge with Banzi virus after they were given rabbit antiserum to mouse thymocytes. Congenic C3H/He mice, which are genetically susceptible to lethal flaviviral infection, were protected from lethal challenge with Banzi virus by adoptive immunization with splenic cells from syngeneric or congenic donor mice infected with live virus, as measured by amelioration of clinical disease, death rates, and viral replication. Protection was dependent on thymus cells; mice given immune splenic cells treated with rabbit antiserum to mouse brain and complement had high death rates. Transfer of protection was dependent on time and the dosage of splenic cells. Immune splenic cells from c3h/rv donors were, on a cell-for-cell basis, more effective than immune splenic cells from C3H/He donors in preventing viral replication, encephalitis, and death in C3H/He recipients.

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PubMed1992

In vivo lymphocyte-mediated myocardial injuries demonstrated by adoptive transfer of experimental autoimmune myocarditis.

BACKGROUND: To elucidate the mechanisms of immune-related myocardial injuries, we examined whether autoimmune myocarditis was passively transferable by use of humoral or cellular factors. METHODS AND RESULTS: Active myocarditis was elicited in Lewis rats by immunization with human cardiac myosin fraction in complete Freund's adjuvant. This experimental myocarditis was characterized by macroscopic features such as pericardial effusion, enlargement of the heart, and gray discoloration of the cardiac surface. Histologically, extensive myocardial necrosis and numerous inflammatory cell infiltrations were observed. Interestingly, multinucleated giant cells were frequently observed in the lesions. Transfer of the disease by the humoral factor was examined by use of fresh sera and immunoglobulin fraction of pooled sera from rats with severe myocarditis, and transfer by the cellular factor was tested by use of spleen cells and lymph node cells from the diseased rats. When naive Lewis rats were given 15.75 mg of immunoglobulin fraction, no particular change was observed in the hearts. Fresh sera also could not elicit myocarditis in recipient rats. In contrast, intravenous injection of spleen cells or lymph node cells that were cultured for 3 days in the presence of 1 microgram/ml of concanavalin A elicited severe myocarditis. The macroscopic and microscopic findings of passively transferred myocarditis are essentially the same as those found in actively induced myocarditis. Multinucleated giant cells were also observed in the lesions of transferred myocarditis. CONCLUSIONS: This study demonstrates direct evidence for in vivo lymphocyte-mediated myocardial injuries.

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PubMed1981

Recovery from experimental rabies by adoptive transfer of immune cells.

The transient, sublethal infection produced by intracerebral inoculation of the Flury high egg passage (HEP) strain of rabies virus into adult mice was converted into a lethal one (approx. 80 to 100% mortality) by administering 150 mg/kg cyclophosphamide (CY) 2 days after infection. Immunosuppressed, infected animals showed no immunological response to rabies and died 15 to 20 days after infection. However, mortality was reduced to 12% when suppressed mice were adoptively immunized, 4 days after infection, with an intravenous injection of 60 X 10(6) spleen cells from rabies-immune syngeneic donors. The lymphocytes obtained early after donor immunization (4 to 11 days) reduced mortality, whereas those obtained late (16 to 32 days after immunization) were not effective. The ability of donor cells to protect animals corresponded very closely with donor cytotoxic T lymphocyte (CTL) activity. Within 4 days after immune cell transfer, serum neutralizing antibody and CTL levels in recipients were comparable to those found in virus-infected control animals. Immune donor cells were fractionated into thymus-derived (T-enriched) and bone marrow-derived (B-enriched) subsets. The T and B subsets reduced mortality to 32% and 34% respectively. CTL and serum neutralizing antibody responses could be detected in these animals, although they appeared later than in mice treated with unfractionated immune spleen cells. The present study demonstrates that both B and T lymphocytes are required for optimum clearance of rabies from the central nervous system (CNS) and suggests a functional role for rabies-specific CTL in vivo.

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PubMed2004

Adoptive transfer of allogeneic Epstein-Barr virus (EBV)-specific cytotoxic T cells with in vitro antitumor activity boosts LMP2-specific immune response in a patient with EBV-related nasopharyngeal carcinoma.

BACKGROUND: The outcome of patients with nasopharyngeal carcinoma (NPC) presenting as advanced-stage disease or failing conventional radio-chemotherapy is poor. Thus, additional forms of effective, low-toxicity treatment are warranted to improve NPC prognosis. Since NPC is almost universally associated with Epstein-Barr virus (EBV), cellular immunotherapy with EBV-specific cytotoxic T lymphocytes (CTLs) may prove a successful treatment strategy. Patient and methods A patient with relapsed NPC, refractory to conventional treatments, received salvage adoptive immunotherapy with EBV-specific CTLs reactivated ex vivo from a human leukocyte antigen-identical sibling. EBV-specific immunity, as well as T-cell repertoire in the tumor, before and after immunotherapy, was evaluated. RESULTS: CTL transfer was well tolerated, and a temporary stabilization of disease was obtained. Moreover, notwithstanding the short in-vivo duration of allogeneic CTLs, immunotherapy induced a marked increase of endogenous tumor-infiltrating CD8+ T lymphocytes, and a long-term increase of latent membrane protein 2-specific immunity. CONCLUSIONS: Preliminary data obtained in this patient indicate that EBV-specific CTLs are safe, may exert specific killing of NPC tumor cells in vitro, and induce antitumor effect in vivo.

Adult↗
PubMed1993

Genetic susceptibility to the induction of murine experimental autoimmune orchitis (EAO) without adjuvant. II. Analysis on susceptibility to EAO induction using F1 hybrid mice and adoptive transfer system.

In our novel murine model of experimental autoimmune orchitis (EAO) induced by two or three injections of viable syngeneic testicular germ cells (TC) alone, significant differences in susceptibility to the induction of EAO were found, and the disease susceptibility did not seem to be associated with a particular H-2 haplotype. The H-2 identical background disparate (highly susceptible x low susceptible)F1 hybrids, (C3H/He x C3H/HeJ)F1 and (C3H/HeJ x C3H/He)F1 mice, were highly susceptible to the induction of EAO. The H-2 identical background disparate (highly susceptible x resistant)F1 hybrids, (C3H/He x C3H/BiKi)F1 and (C3H/BiKi x C3H/He)F1 mice, were low susceptible to the induction of EAO. Both the H-2 and background disparate (highly susceptible x resistant)F1 hybrids, (C3H/He x DBA/2N)F1 and (DBA/2N x C3H/He)F1 mice, were equally resistant to EAO induction. In the susceptible hybrids, both delayed footpad reaction (DFR) and antibody responses to TC increased. On the other hand, in the resistant hybrids, the levels of anti-TC antibodies were elevated but the DFR to TC remains depressed. This suggests that the antibody production and induction of DFR may be under different genetic controls and that cellular immunity plays an important role in this EAO induction. In order to search for the mechanistic basis for low susceptible C3H/HeJ and resistant C3H/BiKi mice, these mice received orchitis-inducible spleen cells (SPCs) from C3H/He mice. C3H/HeJ mice were highly susceptible to passive EAO. In contrast, disease-resistant C3H/BiKi mice failed to develop passive EAO. In addition, we examined whether or not regulatory cells capable of preventing the disease induction were generated in low susceptible C3H/HeJ and resistant C3H/BiKi mice immunized with TC. Transfer of SPCs from TC-immunized C3H/HeJ and C3H/BiKi mice into C3H/He mice before the EAO challenge had no suppressive effect on subsequent disease induction.

Animals↗
PubMed1988

Experimental autoimmune glomerulonephritis in chickens. II. Adoptive transfer of disease with mononuclear cells.

Autoimmune glomerulonephritis was induced in donor chickens by immunization with chicken, human, turkey or bovine glomeruli. Lymphocytes from the kidneys of each group and the spleen of donors immunized with chicken glomeruli were isolated and injected intravenously into six-week old syngeneic SC chickens. The disease was transferred to bursectomized/non-bursectomized recipients by cells from donors immunized with chicken and bovine glomeruli but not by cells from chickens immunized with human and turkey glomeruli. The transferred disease correlated with interstitial infiltrates in donors. No antibody was detected on the glomerular basement membrane or in the circulation of any recipients. Glomerulonephritis in this model can be transferred by specifically sensitized T lymphocytes alone without antibody. This new pathogenic process may play an important role in the development of glomerulonephritis in other animal models as well as in man, where minimal or no immune deposits are observed despite glomerulonephritis.

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PubMedDate not supplied

Immune control of neoplasia by adoptive transfer of macrophages: potentiality for antigen presentation and gene transfer.

Human macrophages could be differentiated from mononuclear precursors present in the blood circulation. After IFN-gamma activation, they became antitumoral and adhered to transformed cells. Low amounts of activated macrophages (MAK) caused regression of experimental tumors in animal models. In cancer patients, MAK were well tolerated and caused tumor necrosis but no clear therapeutic response has been reported up to now. Improvements can be expected using local treatment and more specific macrophages presenting tumor antigens. This restoration of immune recognition of growing tumors with low levels of reactants should ultimately reestablish, after exogenous stimulation, the insufficient immune response of the host against a malignant tumor. Antitumoral macrophages can also be optimized by gene transfection. Macrophages are proposed as stable and long lasting cell vectors for adoptive gene treatments.

Animals↗
PubMed1995

Adoptive transfer of ex vivo activated memory T-cells with or without cyclophosphamide for advanced metastatic melanoma: results in 36 patients.

Autolymphocyte therapy (ALT) is the infusion of autologous peripheral blood mononuclear cells (PBMC) activated ex vivo by a cytokine-rich supernatant (T3CS) generated from a previous autologous lymphocyte culture using low doses of the anti-CD3 mitogenic monoclonal antibody. The mechanism of action is enhancement of a recall response by CD45RO+ (memory) T-cells (ALT cells) to host tumour without dependence on exogenous interleukin (IL)-2. The existence of anti-tumour-specific T-cells in melanoma patients has been well described, and efforts to utilise them therapeutically have achieved modest tumour response rates. However, few long-term survival data have been reported. From 1986 to 1992, we treated 36 patients with disseminated melanoma using ALT alone (26 patients) or adoptive chemoimmunotherapy using ALT and cyclophosphamide (CY) (10 patients). Over this time period, the cell activation method evolved from using cytokine supernatants derived from a one-way allogeneic mixed lymphocyte culture (MLCS), to the current practice of utilising anti-CD3 and autologous cytokines (T3CS). There were 21 men and 15 women, average age 57 years, range 30-82. 27 had failed prior therapies and 9 had no prior therapy. A total of 161 infusion of ALT cells were given: 65 with cells activated in MLCS and 96 with T3CS. There were no grade 3 adverse events, and an approximate 20% incidence of grades 1 and 2 reactions to ALT-cell infusions. Transient cytopenias were seen in patients receiving CY. Sixty-one per cent (22/36) of patients received the planned six ALT-cell infusions, while 39% did not due to progressive disease. In 33 evaluable patients, there were four complete responses, four partial responses and 6 patients with stable disease (SD). Responding patients and those with SD had prolonged survival compared to historical controls when matched for number of organ systems involved. Ex vivo depletion of CD45RO+ T-cells revealed preferential lysis of autologous and HLA-A-matched melanoma targets that was dependent on these memory T-cells. These data suggest that adoptive cellular therapy using ex vivo activated memory T-cells with and without CY is active, has low toxicity, is tumour-specific and can result in clinical benefit in patients with disseminated melanoma.

Adult↗
PubMed1987

Adoptive transfer of immunity to Treponema pallidum Nichols infection in inbred strain 2 and C4D guinea pigs.

T lymphocytes purified from lymph nodes and spleens of chancre-immune, inbred strain 2 guinea pigs, when infused into syngeneic guinea pigs, conferred protection against challenge with Treponema pallidum subsp. pallidum Nichols. No protection was conferred by similar injections of cell suspensions from normal guinea pigs or guinea pigs immunized with T. phagedenis biotype Reiter or T. pallidum-free testis supernatants from infected rabbits. Similar results were obtained with homozygous C4D guinea pigs. After several months of infection, 2 of 11 strain 2 and 1 of 8 strain C4D recipients of T. pallidum-immune cells developed an erythematous reaction of short duration at the injection site; 2 of these recipients were positive for T. pallidum. Throughout the experimental period the humoral response to treponemal antigens was substantially lower in the adoptively immune guinea pigs than in various unprotected control groups. Passive immunity to infection with T. pallidum, however, seems to be dose related, since asymptomatic infection persisted for as long as 3 months after challenge in strain 2 guinea pigs transfused with 10(8) T. pallidum-immune lymphocytes, but not in C4D recipients of twice as many immune cells.

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