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PubMed1982

Study on cellular events in postthymectomy autoimmune oophoritis in mice. I. Requirement of Lyt-1 effector cells for oocytes damage after adoptive transfer.

Neonatal thymectomy during the critical period, 2-4 d after birth, can induce various organ-specific autoimmune diseases including oophoritis in A/J mice. The oophoritis thus induced was passively transferred into neonatal mice by injection of spleen cells obtained from syngeneic donors with the disease. Recipient ovaries were rapidly damaged with remarkable mononuclear cell infiltration and destruction of follicular structures. The phenotype of effector cells responsible for successful adoptive transfer was found to be Thy-1+, Lyt-1+,23-, Ia-, Qa-1-, and was sensitive to antithymocyte serum treatment but resistant to cyclophosphamide treatment or in vitro X-ray irradiation. The compatibility between donor and recipient at the major histocompatibility complex was not required for the effector phase of transfer. The oophoritis induced in BALB/c (nu/+ or +/+) was also shown to be transferred into athymic BALB/c nude mice with resulting ovarian lesion and circulating autoantibodies against oocytes. In this transfer system, the effector cells were also demonstrated to be T cells with the Lyt-1+,23- phenotype. Adoptive transfer experiments in both systems revealed that the destruction of ovaries in postthymectomy autoimmune oophoritis was mediated by Lyt-1 T cells. Whether these T cells can be distinguished from other Lyt-1 cells, such as T helper cells and effector T cells in delayed-type hypersensitivity (DTH), is not clear at present, but the results suggest that the effector mechanisms may be closely related to a DTH reaction.

Animals↗
PubMed1992

Anti-CD2 monoclonal antibodies prevent spontaneous and adoptive transfer of diabetes in the BB/Wor rat.

We studied the effects of anti-CD2 monoclonal antibodies (MAb) on spontaneous and induced autoimmune diabetes mellitus in diabetes-prone (DP) and diabetes-resistant (DR) BB/Wor rats. In DP rats, all anti-CD2 MAb prevented spontaneous diabetes and the adoptive transfer of diabetes with Con-A--stimulated acute diabetic spleen cells; OX34 prevented Poly I:C induced accelerated onset of diabetes and the adoptive transfer of diabetes with Con-A--stimulated RT6.1+ T cell depleted DR splenocytes. In DP rats, all anti-CD2 MAb except OX53 depleted CD4+ T cells, without depleting natural killer cells or CD8+ T cells. OX34 injected DR rats were profoundly depleted of CD4+ T cells without evidence of decreased CD8+ T cells, but were not protected against the induction of diabetes by RT6.1+ T-cell depletion and Poly I:C injections. We conclude that anti-CD2 MAbs protect against BB/Wor autoimmune diabetes by depleting CD4+ T cells, preventing the activation of effector cells, or by blocking CD2/ligand interaction between effector and target cells.

Animals↗
PubMed1979

Adoptive transfer of cross-protection among alphaviruses in mice requires allogeneic stimulation.

Cell-mediated (T-effector cell) immunity is proposed as playing the major role in cross-protection between Sindbis and Semliki Forest viruses, which are alphaviruses that do not elicit cross-neutralizing antibodies. In adoptive transfer experiments, T-cells from spleens of Sindbis virus-immunized mice were found to confer specific cross-protection to Semliki Forest virus upon recipient mice. This cross-protection was observed in the outbred ICR strain of mice and when transfers were made between several combinations of inbred and hybrid strains. Cross-protection was substantially reduced if syngeneic rather than allogeneic cell transfers of one spleen equivalent per mouse were made. The results suggest that allogeneic stimulation (mixed lymphocyte reaction in vivo) is necessary to increase the number of effector cells (donor) in the recipient. This was supported by the observation that blastogenic stimulation of donor cells in vitro by concanavalin A induces cross-protection in syngeneic animals. Conversion of recipient cells to specific effector cells also appears to play a role in protecting mice against Semliki Forest virus. This was concluded from the experiments described above, a time course study, and the results of experiments that involved serial passages of transferred cells across histocompatibility barriers. Thus, we propose that both donor and recipient cells are active in protecting recipient mice against challenge with Semliki Forest virus after adoptive transfer.

Animals↗
PubMed1994

Immunomodulation in patients with epithelial ovarian cancer after adoptive transfer of tumor-infiltrating lymphocytes.

The immunomodulation determined by natural killer cell activity, delayed-type hypersensitivity to purified protein derivative and phytohemagglutin, and phenotypic changes of peripheral blood lymphocytes was characterized in 12 patients with epithelial ovarian cancer who received adoptive transfer of tumor-infiltrating lymphocytes (TILs) after cisplatin-containing chemotherapy (TIL group). As a control, 10 patients with epithelial ovarian cancer who did not receive infusions of TIL were also examined in the same fashion. In the TIL group, peripheral blood lymphocytes showed increased percentages of cells bearing the CD8 antigen, in contrast to stable percentages of CD4 antigen-bearing cells, resulting in a decreased ratio of CD4+ to CD8+ cells. The percentages of CD16 and CD56 antigen-bearing cells also increased in proportion to augmentation of natural killer cell activity against K562 cells. Additionally, with regard to cell-mediated immunity determined by delayed-type hypersensitivity to phytohemagglutin and purified protein derivative, significantly and slightly enlarged erythema was observed 2 and 8 weeks, respectively, after the injection of TILs (phytohemagglutin, P < 0.05; purified protein derivative, not statistically significant). The control group showed no major changes in any of the immunological markers. These results suggest the possibility that the adoptive transfer of TILs induces immunoactivation of cellular immunity and enhances natural killer activity in patients with epithelial ovarian cancer.

Adult↗
PubMed2000

Adoptive immunotherapy in patients with recurrent malignant glioma: preliminary results of using autologous whole-tumor vaccine plus granulocyte-macrophage colony-stimulating factor and adoptive transfer of anti-CD3-activated lymphocytes.

OBJECT: This trial was designed to determine the ability of autologous whole-tumor cell vaccines to induce cell mediated immune responses in patients with recurrent malignant glioma, as well as to determine whether combining such vaccination with adoptive transfer of in vitro activated T lymphocytes prolongs patient survival. METHODS: Nineteen patients with recurrent malignant glioma, in whom previous external beam radiotherapy and at least one course of chemotherapy had failed were vaccinated twice with irradiated autologous whole tumor cells by using granulocyte-marcrophage colony-stimulating factor as an adjuvant. Patients then underwent leukapheresis followed by adoptive transfer of peripheral blood lymphocytes activated in vitro with anti-CD3 and interleukin-2. In vivo immune response, radiological response, clinical outcome, and survival were monitored. Seventeen patients developed a delayed-type hypersensitivity (DTH) response to vaccination that appeared to be directed against the autologous tumor. In eight patients there was radiological evidence of a response and in five there was evidence of clinical improvement. Median survival was 12 months (range 6-28 months), and both the presence of a DTH response and the radiological response correlated with survival (p < 0.02 and p < 0.04, respectively). CONCLUSIONS: These preliminary results suggest that autologous whole-tumor cell vaccines induce a cell-mediated immune response, which appears to be tumor specific in most patients. Furthermore, vaccination combined with adoptive immunotherapy with in vitro activated cells may induce a radiologically demonstrated tumor response and improved survival despite a condition of advanced disease and immunosuppression resulting from previous treatment or tumor burden. Further studies of immunotherapy are warranted.

Adjuvants, Immunologic↗
PubMed1996

Cancer prevention by adoptive transfer of antigen 60-activated immunocompetent cells.

The authors have already shown that A60, the thermostable macromolecular antigen complex of Mycobacterium bovis BCG, induced resistance to tumour challenge in several murine systems. In the present work, the authors provided evidence that activated macrophages played a major role, and cytolytic T lymphocytes a minor one, in both in vivo and in vitro A60-promoted cancer cell cytolysis. To identify the types of immunocompetent cells involved in this protective effect, macrophages and T lymphocytes from A60-primed mice donors were adoptively transferred to irradiated recipients prior to EMT 6 tumour challenge. In some groups, A60-primed donors were survivors of previous tumour challenges. Transfer of T lymphocytes from the spleen or lymph-nodes of A60-immunized mice induced 80-90% protection against tumour challenge. Conversely, transferred macrophages, although cytolytically active, did not induce resistance to tumour implantation. Furthermore, adoptive transfer with T lymphocytes from A60-immunized and EMT 6 challenge-surviving donors induced 100% protection. It is concluded that stimulation of T lymphocytes by A60 is the key step which leads to activation of the immunocompetent cells involved in tumour rejection.

Animals↗
PubMedDate not supplied

Resolution of murine chlamydial genital infection by the adoptive transfer of a biovar-specific, Th1 lymphocyte clone.

MoPn-specific T-cell clones were isolated from a T-cell line that was capable of curing chlamydial genital infection by the Chlamydia trachomatis agent of mouse pneumonitis (MoPn) after adoptive transfer. Two clones (designated as 2.14-0 and 2.14-3) were characterized by flow cytometry techniques to be homogenous for L3T4, CD3, and alpha/beta T cell receptor (TcR) T-helper cell markers. The two clones were biovar specific, because they reacted to MoPn but not the Chlamydia psittaci agent of guinea pig inclusion conjunctivitis (GPIC) or C. trachomatis, serovar type E. Cytokine profile analysis, by a combination of bioassays, ELISA, and slot/Northern blotting for specific cytokine messenger RNAs, further revealed that cultures of antigen-stimulated clone 2.14-0 contained interleukin-2 (IL-2), tumor necrosis factor-alpha, and gamma interferon (a T helper 1 cell [Th1] profile). Clone 2.14-3 was also positive for gamma interferon, a level much lower than that of clone 2.14-0, and negative for IL-4 secretion, suggesting a Th1 profile as well. The ability of these clones to bring about the resolution of the chronic genital chlamydial infection of nude mice was tested by the adoptive transfer of 10(7) cells of each clone into the mice. By 4 weeks after cell transfer of clone 2.14-0, 81% of recipient nude mice (30 of 37) resolved the disease. In contrast, clone 2.14-3 or a control T-cell clone specific for a heterologous antigen were unable to resolve the infection in 20 recipients in each case, even after 100 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Adoptive transfer of fluorescence-labeled cells shows that resident peritoneal macrophages are able to migrate into specialized lymphoid organs and inflammatory sites in the mouse.

We have examined the migration of murine macrophages from the vascular compartment to normal and inflammatory tissues by the adoptive transfer of resident peritoneal macrophages (RPM phi) fluorescently labeled with the hydrophobic dye 1,1'-dioctadecyl 3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI). After initial labeling of the plasma membrane of RPM phi, the dye accumulated stably in intracellular vesicles of low density (rho = 1.042-1.045 kg/l) and cells remained viable in culture for 4 weeks. Like the normal monocyte, DiI-RPM phi, but not exudate-derived or fixed cells, migrated to peritoneal exudates, following i.v. adoptive transfer, by a mechanism inhibitable by an antibody to the type 3 complement receptor. In the absence of an inflammatory stimulus there was no migration to the peritoneal cavity, and DiI-RPM phi accumulated within 4 h in the red pulp and marginal zone of the spleen. By day 6 these cells still formed a tight ring of fluorescence in the marginal zone alone, outside the marginal metallophil cells. DiI-RPM phi injected into the peritoneal cavity migrated to the parathymic lymph nodes where they were found in the subcapsular sinus and in the medullary cords, whereas very few fluorescent cells could be found in the T cell areas. The migration of RPM phi to lymphoid organs required viable cells but, unlike the recruitment of cells to peritoneal exudates, was not inhibitable by antibodies to CR3. We conclude that the RPM phi is a useful surrogate for the analysis of constitutive and induced monocyte migration to secondary lymphoid and inflammatory sites, respectively.

Animals↗
PubMed1989

Acquisition by the murine host of responsiveness toward various neoplastic cell lines, but not toward self, through adoptive transfer of a helper T-lymphocyte clone with antiself specificity.

Self-antigens, when expressed on neoplastic cells, have been shown to exhibit a certain antigenicity. We attempted to apply this antigenicity to enhance antitumor immune responses. Cells from the syngeneic, CD4+, CD8-, helper T-lymphocyte clone TE2 were adoptively transferred to C57BL/6 mice. TE2 lymphocytes recognize a self-antigen on splenocytes that is expressed aberrantly on the neoplastic cell lines EL4/8, EL4/13, B16-BL6, and PG19, all of C57BL/6 origin. Their adoptive transfer led to the rejection by the host of the former neoplastic cells and of 3LL carcinoma cells, administered 2 months later; inocula 40 to 80 times the minimal lethal size were rejected and conveyed to the mice a 10-fold enhanced cytotoxic T-lymphocyte response. Despite the autoimmune responsiveness of the TE2 T-lymphocytes, no graft-versus-host reaction was apparent. This conclusion is based on the absence of a polyclonal B-lymphocyte stimulation in the host, the stable number of residual donor TE2 cells, and the general health of the recipient mice. Consequently, the autoimmune and tumor-responsive TE2 cells, transplanted into the immune environment of the host, exhibit a specificity that is restricted toward neoplastic cells.

Animals↗
PubMed2004

Regression of bone metastases following adoptive transfer of anti-CD3-activated and IL-2-expanded tumor vaccine draining lymph node cells.

As many as 80% of patients with breast, prostate, or lung cancer develop bone metastases during the course of their illness. However, thus far, no attempts have been made to explore the potential value of adoptive immunotherapy with antigen-specific T lymphocytes specifically for the treatment of skeletal metastases. Here, we demonstrate tumor regression in a preclinical model of bone metastases from the murine B16BL6 melanoma following adoptive transfer of effector T lymphocytes obtained from tumor vaccine draining lymph nodes. The antitumor effect required transfer of high number of effector cells, which was dependent on CD8+ cells as demonstrated by in vivo depletion of different T cell subsets, and was magnified if effector cells were administered to the arterial supply of the bone/bone marrow. Using flow cytometric analysis, CFSE-labelled Thy1.1+ donor T cells were isolated from the bone marrow of tumor-bearing mice at 24 h and 6 days following adoptive transfer. At the latter time point cell division of the transferred effector cells was detectable. Currently, no curative treatment is known for skeletal metastases in clinical practice. Considering the promising early findings in the present study, further studies exploring the therapeutic potential of adoptive immunotherapy for metastatic disease to the skeleton are warranted.

Animals↗
PubMed1999

Factors affecting adoptive transfer of resistance to Schistosoma mansoni in the snail intermediate host, Biomphalaria glabrata.

We examined potential variables affecting adoptive transfer of resistance to Schistosoma mansoni in Biomphalaria glabrata implanted with amebocyte-producing organs (APOs) from resistant snails. Transplants of 7 tissues other than the APO (heart, kidney, mantle, albumin gland, brain, digestive gland, and gonad) did not transfer resistance, suggesting a unique property of this structure. Only APOs from donors previously exposed to miracidia transferred resistance, although whether this is evidence for a priming effect or merely the elimination of susceptible donors is not known. Variability in the donor and in the implant itself apparently was unimportant, inasmuch as implants from small or large snails or from 2 separate donors all conferred similar levels of resistance. Recipients of APOs from 2 additional resistant strains of B. glabrata, 10-R2 and Salvador, also displayed resistance. However, no resistance was transferred by APOs from schistosome-refractory B. obstructa. Histological examination of implants removed from recipients that either did or did not show transferred resistance revealed no differences in mitotic activity. Furthermore, implanted APOs from B. obstructa displayed no mitotic activity. Finally, reexposure of snails with transferred resistance to a large dose of miracidia caused infection in 70%, suggesting that either transferred resistance is transitory or it can be overwhelmed.

Adoptive Transfer↗
PubMed1994

Reversal of acute myelogenous leukemia in humanized SCID mice using a novel adoptive transfer approach.

Advanced human malignancies cannot be permanently cured by adoptive transfer of autologous lymphokine-activated killer (LAK) cells. Moreover, administration of high doses of IL-2 to maintain LAK activity in vivo is associated with severe toxicity. In this study, we tested the anti-tumor efficacy of a uniquely potent MHC non-restricted human killer T cell clone (TALL-104) in humanized severe combined immunodeficient (SCID) mice bearing acute myelogenous leukemia (AML). We show that, in appropriate experimental conditions, TALL-104 cells could effectively reverse the aggressive growth of the myelomonocytic leukemia cell line U937 in SCID mouse tissues, leading to complete abrogation of AML. A single transfer of TALL-104 cells at the time of tumor challenge in combination with recombinant human (rh) IL-12 (1 microgram/d) prolonged significantly the life of the mice. However, eradication of leukemia, as monitored both clinically and by PCR, was achieved by repeated injection of the effectors at close intervals. Complete cure was obtained also upon transfer of lethally irradiated (non-proliferating) TALL-104 cells together with low doses of rh IL-2 (100 U/d). Most notably, of the mice that received multiple transfers of TALL-104 cells without cytokines in an advanced disease stage, 50% were clinically cured, and 50% survived significantly longer. The potential of TALL-104 cells as an effective and safe leukemia purging agent is discussed.

Animals↗
PubMed1975

Enzymatic modification of lymphocyte receptors for antigen III. loss of antigen-responsiveness with recovery after adoptive transfer.

Spleen cells from bovine serum albumin (BSA)-primed CBA mice were exposed to proteolysis by papain and pronase under conditions where cell recovery and viability were not impaired but surface Ig and antigen-binding were greatly reduced. The ability of the cells to respond to BSA was tested by a modified Farr assay of serum taken 10 days after adoptive transfer of cells to lethally irradiated syngeneic recipients. Cells not exposed to enzymes were able to respond to BSA either in vitro before adoptive transfer or in vivo after transfer. Cells exposed to papain and pronase were unable to respond in vitro, but normal antibody production was approached when the cells were exposed to antigen in vivo. Thus, after removal of much surface Ig the cells were temporarily unresponsive to antigen but were still functional, as demonstrated by their ability to recover responsiveness in vivo.

Animals↗
PubMed1994

Adoptive transfer of cloned T helper cells ameliorates periodontal disease in nude rats.

We have previously described a T helper cell 2-type clone, A3, of rat T cells that provides help for antibody production to Actinobacillus actinomycetemcomitans in vitro and in vivo in normal (euthymic) isogeneic Rowett strain recipient rats. Adoptive transfer of this T helper cell clone to euthymic rats also protects them from periodontal bone loss induced by oral infection with A. actinomycetemcomitans. In the present study, to assess the cell requirement for protection, A3 clone T lymphocytes (10(6)) or naive lymph node (6 x 10(4)) T cells, or A3 plus naive lymph node T cells (6 x 10(4)) were adoptively transferred to groups (n = 7-9) of 30-day-old Rowett athymic nude (rnu/rnu) rats. All recipients were also immunized (intraperitoneally) with 10(7) killed A. actinomycetemcomitans on the day of T cell transfer and orally infected with these bacteria on each of the next 5 days. Recipients of the combined A3+lymph node T cell transfer showed significantly increased serum immunoglobulin G (IgG) and IgM antibody to A. actinomycetemcomitans and in vitro proliferation of spleen lymphocytes to A. actinomycetemcomitans as antigen compared with nude animals receiving lymph node T cells only. Although other possibilities are discussed, we inferred that these differences might be due to successful population of the congenitally athymic rats by A3 clone cells given with a small number of normal autologous naive lymph node T cells. The result of this co-transfer of naive T cells with the A3 clone cells seemed to be greatly increased antibody production and protection from periodontal bone loss.

Aggregatibacter actinomycetemcomitans↗
PubMed1996

Long-term restoration of immunity against Epstein-Barr virus infection by adoptive transfer of gene-modified virus-specific T lymphocytes.

Adoptive transfer of antigen-specific cytotoxic T lymphocytes (CTLs) offers safe and effective therapy for certain viral infections and could prove useful in the eradication of tumor cells. Whether or not the infused T cells persist for extended periods, retaining their ability to expand in response to antigenic stimulation, is not known. We now report long-term detection of gene-marked Epstein-Barr virus (EBV)-specific CTLs in immunocompromised patients at risk for the development of EBV lymphoproliferative disease. Infusions of CTLs not only restored cellular immune responses against EBV, but also established populations of CTL precursors that could respond to in vivo or ex vivo challenge with the virus for as long as 18 months. Our findings support wider use of antigen-specific CTLs in adoptive immunotherapy.

Bone Marrow Transplantation↗
PubMed1992

Influence of age on the induction of oral tolerance in mice and its adoptive transfer by spleen cells.

1. Seven-week-old B6D2F1 mice were highly susceptible to the induction of oral tolerance to ovalbumin (Ova), whereas 70-week-old mice were totally refractory. 2. Immune responsiveness (secondary antibody formation) to intraperitoneal immunization to Ova was the same in 7-week- or 70-week-old B6D2F1 mice. 3. In B6D2F1 mice, the adoptive transfer of spleen cells from old donors into young recipients hindered, and, reciprocally, transfer of spleen cells from young donors into old recipients facilitated the induction of oral tolerance. 4. In BALB/c mice, which are refractory to oral tolerance to Ova, the adoptive transfer of spleen cells from neonate or young donors into old recipients failed to modify the lack of susceptibility to the induction of oral tolerance.

Aging↗
PubMed2006

Adoptive transfer of Epstein-Barr virus-specific cytotoxic T-lymphocytes for the treatment of angiocentric lymphomas.

Angiocentric lymphoma, known as natural killer (NK)/T-cell non-Hodgkin's lymphoma, has been reported to be associated with the Epstein-Barr virus (EBV). We performed adoptive transfer of EBV-specific polyclonal T-cell lines in 3 patients with extranodal NK/T-cell lymphoma, nasal type, and evaluated the treatment for safety, immunologic reconstitution, and clinical outcomes. The tissue samples collected from the 3 patients were confirmed by polymerase chain reaction analysis to be EBV positive. In the cases of the first and second patients, EBV-transformed B-lymphoblastoid cell lines (LCLs) and T-cell lines were generated from peripheral lymphocytes of HLA-matched sibling donors. The third patient's T-cell lines were induced with autologous lymphocytes. Polyclonal T-cell infusion was carried out after high-dose radiotherapy because active relapsed disease remained in all of the patients. The first patient received 4 weekly infusions of 2 3 10(7) cells/m(2), and the second and third patients underwent treatment with 2 cycles of infusions of the same dosage. All T-cell lines showed >60% NK activity, cytotoxic T-lymphocyte (CTL) responses of >40% against autologous LCLs, and no CTL activity against patient-derived lymphoblasts. The level of cytotoxicity increased substantially in all patients after cell infusion. The 2 patients who received T-cell therapy twice had stabilized disease for more than 3 years. These safe treatments exhibited no severe inflammatory response, and no serious toxicity developed during T-cell therapy. Our findings demonstrate that adoptively transferred cells may provide reconstitution of EBV-specific CTL responses in patients with active relapsed angiocentric lymphoma. These results provide a rationale for the immunotherapy of angiocentric lymphoma.

Adult↗
PubMed1997

Clearance of hepatitis B surface antigen after bone marrow transplantation: role of adoptive immunity transfer.

Adoptive immunity transfer has been reported to be effective in clearing chronic hepatitis B virus (HBV) infection. Two hundred twenty-six patients who received allogeneic bone marrow transplantation (BMT) between May 1990 and September 1995 were screened for hepatitis B markers. Twenty-one patients were hepatitis B surface antigen (HBsAg) positive before BMT. The median follow-up period was 20 months (range, 2-59 months). Two of these patients had sustained clearance of HBV infection after transplantation. Both patients were hepatitis B e antigen (HBeAg)-negative, hepatitis B e antibody (anti-HBe)-positive, and serum HBV DNA-negative (by dot-blot hybridization) before BMT. Both had a flare in the serum alanine transaminase (ALT) level around the time of HBsAg clearance. Sustained clearance of HBsAg was observed in 2 of the 5 patients who received hepatitis B surface antibody (anti-HBs)-positive marrow but in none of the 16 patients who received anti-HBs-negative marrow (P < .05). One additional patient who received anti-HBs-positive marrow had transient HBsAg seroconversion. Among the 18 patients who remained persistently HBsAg-positive after BMT, 3 had HBeAg seroconversion and 3 had reversion to HBeAg positivity. In this study, we found a significant association between clearance of HBV infection and anti-HBs-positive bone marrow donors. Adoptive immunity transfer is effective in clearing HBV from patients with chronic HBV infection.

Adolescent↗