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PubMed1981

Adoptive transfer of experimental allergic encephalomyelitis in SJL/J mice after in vitro activation of lymph node cells by myelin basic protein: requirement for Lyt 1+ 2- T lymphocytes.

Optimal conditions were established for the adoptive transfer of experimental allergic encephalomyelitis (EAE) in SJL/J mice. Lymph node cells from SJL/J mice primed in vivo with myelin basic protein (BP) were incubated in vitro with BP. These cells proliferated specifically to BP and when transferred at the optimal conditions into syngeneic mice induced EAE in 100% of the recipients. The in vitro proliferative response to BP was dependent on the presence of Lyt 1+ 2- T lymphocytes. Furthermore, when the activated LNC were treated before transfer with anti-Thy 1 or anti-Lyt 1 antibody and C, neither clinical nor histologic signs were observed in the recipients, whereas treatment with anti-Lyt 2 antibody and C had no effect. These results indicated that Lyt 1+ 2- T cells are responsible for the transfer of EAE.

Animals↗
PubMed1983

Protection of mice from fatal herpes simplex virus type 1 infection by adoptive transfer of cloned virus-specific and H-2-restricted cytotoxic T lymphocytes.

A cloned culture of secondary anti-herpes simplex virus (anti-HSV) cytotoxic T lymphocytes (CTL) generated in vitro when adoptively transferred to intact or cyclophosphamide (CP) pretreated syngeneic mice protected the recipients from death following intraperitoneal infection with HSV-1. This in vivo protective effect conferred by anti-HSV CTL was virus-specific and H-2K/D-restricted. Twenty-four h after HSV-1 infection of BALB/c mice (intact or CP-pretreated) relatively high levels of serum interferon-gamma were observed in the recipients of syngeneic anti-HSV CTL and this event may explain, at least in part, the CTL-mediated protective effect.

Animals↗
PubMed1984

Adoptively transferred chronic relapsing experimental autoimmune encephalomyelitis in the mouse. Neuropathologic analysis.

The fine structure is described of a new model of chronic relapsing experimental allergic encephalomyelitis in the SJL/J mouse induced by the single adoptive transfer of myelin basic protein-sensitized lymph node cells. The neuropathology of the condition compared favorably with that seen in other species, and unlike a similar disease in the same strain of mouse induced by active sensitization with a central nervous system emulsion, there was little axonal pathology. Typical of mouse experimental allergic encephalomyelitis was the consistent involvement of polymorphonuclear leukocytes and extravasated material in central nervous system lesions. Remissions showed remyelination to be the major feature in the central nervous system, and clinical relapses were matched pathologically by fresh waves of inflammation and demyelination. Unusually large, apparently organized, sinusoidal collections of lymphoid cells (some of them displaying evidence of proliferation) were seen in the periventricular areas of the brain. The ability to induce chronic relapsing demyelination by passive means indicates that an antigen depot is not necessary for the perpetuation of the disease which is possibly transferred by memory cells in the inoculum. This model has virtue in its applicability to the pathogenesis and therapy of multiple sclerosis.

Animals↗
PubMed1995

Adoptive transfer of experimental hypersensitivity pneumonitis in the LEW rat.

The pathogenesis of immune-mediated pulmonary inflammation following inhalation of antigen in sensitized subjects may involve specific cellular or humoral mechanisms, or both. We used adoptive transfer to document cellular mechanisms in an established LEW rat model of acute hypersensitivity pneumonitis. The optimal protocol utilized sensitized spleen cells cultured for 72 h in the presence of antigen and concanavalin A before intraperitoneal injection of 20 x 10(6) cultured cells into sublethally irradiated recipients. Experimental and control rats were subjected 7 d later to twice daily aerosol challenge for 1 or 3 d and examined 12 h after the last challenge. Histopathology was evaluated in one lung, and the other was lavaged and cells evaluated by flow cytometry for T cell phenotypes (CD4, CD8, and RT6, CD45R subsets). Histopathology and cell numbers for most phenotypes were increased in experimental over controls, but proportions were unchanged. Similar results were obtained in animals evaluated at both 24 and 72 h after initial challenge. Results indicate cellular participation in an established LEW rat model of HP. Significant increases in numbers of T cell phenotypes suggest an important role in pathogenesis, but no single phenotype could be incriminated by disproportionate numbers.

Alveolitis, Extrinsic Allergic↗
PubMed1993

Enhancing effects of irrelevant lymphocytes on adoptive transferred experimental allergic encephalomyelitis.

To help understand effector mechanisms in experimental allergic encephalomyelitis (EAE) we examined the effects of adding 'irrelevant' lymphocytes from non-EAE donors to major basic protein (MBP)-reactive lymphocytes in the adoptive transfer of EAE (Tr-EAE). The intravenous injection of tetanus toxoid-reactive lymphocytes (TT-cells) and phytohemagglutinin-stimulated lymphocytes on the same day or 2 days after intra-arterial injection of MBP-reactive lymphocytes enhanced the clinical and pathological expression of Tr-EAE. In lymphocyte trafficking studies there was significant accumulation of these injected TT-cells in the central nervous system during enhanced transfer of EAE. W3/25-positive cells were much more predominant in lesion of central nervous system when reinjected with TT cells along with MBP cells compared with lesions of rats injected with MBP cells alone. These findings suggest possible participation of lymphocytes other than MBP-reactive cells in the expression of EAE and provide a useful model to further explore effector mechanisms in the future.

Animals↗
PubMed1993

Adoptive transfer of immunity to oral challenge with virulent salmonellae in innately susceptible BALB/c mice requires both immune serum and T cells.

The mechanisms of immunity to salmonellae conferred by immunization with live vaccines were studied by adoptive transfer using the mouse-virulent strain Salmonella typhimurium C5 and innately susceptible BALB/c (ltys) mice. This organism cannot establish a sublethal infection in naive BALB/c mice. Animals immunized 2 to 3 months earlier with the S. typhimurium SL3261 aroA live vaccine were used as donors of serum, spleen cells, and mesenteric lymph node cells for naive recipients which were challenged orally with the virulent C5 strain. Simultaneous transfer of both immune serum and immune cells was necessary for protection. Simultaneously depleting the donors of CD4+ and CD8+ T cells by administration of antisera in vivo prior to cell harvesting showed that T cells were necessary for protection. The results demonstrate that both antibody and T cells are required for recall of immunity to oral challenge with virulent salmonellae in innately susceptible mice and suggest that the ability to elicit opsonizing antibody in addition to cell-mediated immunity is important for optimal protection induced by salmonella vaccines.

Animals↗
PubMed1996

Transcutaneous photodynamic therapy alters the development of an adoptively transferred form of murine experimental autoimmune encephalomyelitis.

Transcutaneous photodynamic therapy (PDT), utilizing benzoporphyrin derivative monoacid ring A (BPD, verteporfin) and whole-body light exposure, was assessed for its capacity to modify the course of adoptively transferred experimental autoimmune encephalomyelitis (EAE) in PL mice. Using a novel cell culture technique to facilitate the induction of this neurodegenerative condition, disease signs commenced 3-4 weeks after the transfer of myelin basic protein (MBP)-reactive lymph node or spleen cells to naive syngeneic recipients. Mice administered MBP-sensitized lymph node cells preincubated with BPD followed by whole-body 690 nm light irradiation (15 J/cm2) did not display symptoms of EAE. Although almost all animals given MBP-sensitized spleen cells developed EAE, mice given BPD (1 mg/kg) and the light treatment 24, 48 or 120 h after spleen cell transfer exhibited significantly less severe disease symptoms than control animals. Mice given the photodynamic treatment 24 h after spleen cell transfer also exhibited a significantly later disease onset than the control animals. Treatment of mice with PDT 24 h prior to spleen cell transfer did not influence subsequent disease severity but modestly delayed its onset. In the absence of directed light, BPD did not influence the development of EAE. Spinal cord tissues were evaluated for the presence of T cell receptor (TCR) V alpha 4 mRNA transcripts that specifically encode for the TCR alpha-chain of MBP-reactive T cells of PL mice. Using the polymerase chain reaction, V alpha 4 TCR mRNA transcripts were present in spinal cord samples prepared from almost all control mice but in only about one-half of spinal cord samples prepared from mice treated with PDT 24 h after spleen cell transfer. These observations indicated that PDT had limited the expansion of MBP-specific V alpha 4+ T cells within the central nervous system. Transcutaneous PDT represents a new technique with which to approach the treatment of autoimmune disease.

Animals↗
PubMed1987

Mouse peritoneal cells activated with a combination of indomethacin, poly I:C and Syncumar inhibit the take of Lewis lung carcinoma in adoptive transfer assay.

Effect of peritoneal cells (PC) from mice treated with a combination of drugs (indomethacin, poly I:C and Syncumar) on the take of Lewis lung (LL) carcinoma was studied in Winn-type adoptive transfer experiments. Transfer of PC from mice given a single intraperitoneal injection of polyinosinic-polycytidylic acid (poly I:C) or indomethacine or Syncumar (100 micrograms of each) per se did not suppress the take of Lewis lung carcinoma in the recipient mice. PC obtained from mice treated with a combination of indomethacin and poly I:C or poly I:C and Syncumar also failed to inhibit the take of the tumour. In contrast, PC collected from mice after a combined treatment with the three drugs (indomethacin + poly I:C + Syncumar) resulted in a 30-60% decrease in tumour take depending on the tumour cell/PC ratio. This effect could not be observed when a single intraperitoneal dose of cyclophosphamide was administered three days before starting of the combined treatment of the donor mice. The effector cells contributing to the tumour inhibitory effect proved to be nonadherent cells, probably large granular lymphocytes (LGL), as their suppressive effect was abrogated after treatment with the lysosomotrop vital dye neutral red.

Acenocoumarol↗
PubMed1993

Prevention and reversal of adoptively transferred, chronic relapsing experimental autoimmune encephalomyelitis with a single high dose cytoreductive treatment followed by syngeneic bone marrow transplantation.

A chronic relapsing form of experimental autoimmune encephalomyelitis (CR-EAE) was induced in SJL/J mice by adoptive transfer of lymph node cells (LNC) sensitized to guinea pig myelin basic protein (GMBP). We examined the efficacy of high dose immunosuppressive regimens (cyclophosphamide [CY] 300 mg/kg or total body irradiation [TBI] 900 cGy) followed by syngeneic bone marrow transplantation (SBMT) in prevention and treatment of already established CR-EAE. Treatment with TBI and SBMT on day 5 after the induction of CR-EAE, just before the onset of clinical signs, completely inhibited the appearance of the paralytic signs. The same treatment, applied 4 d after the clinical onset of the disease, led to a significant regression of the paralytic signs and to a total inhibition of spontaneous relapses during a follow-up period of 2 mo. Challenge of mice with GMBP+CFA 78 d after the passive induction of CR-EAE induced a relapse of the disease 7 d later in almost all of the untreated mice; in contrast, the same challenge given to TBI+SBMT-treated mice caused a delayed relapse (30 d later) in only a minority (3/7) of the challenged mice. In vitro lymphocytic proliferative responses to GMBP and purified protein derivative were significantly lower in TBI/SBMT-treated mice before and after the GMBP challenge, although these mice were fully immunocompetent, as evidenced by their normal lymphocytic proliferation to concanavalin A (ConA) and the FACS analysis of their lymphocytic subpopulations. A similar beneficial therapeutic effect was observed in mice treated with CY followed by SBMT, after the onset of CR-EAE. Our results could support possible clinical applications of similar therapeutic strategies, involving acute immunosuppression followed by stem cell transplantation and retolerization of the reconstituting immune cells in life-threatening neurological and multisystemic autoimmune diseases.

Animals↗
PubMed1992

Adoptive transfer of the entire gld (generalized lymphoproliferative disease) syndrome in nude beige mice by a single gld thymocyte graft.

C57BL/6 nude beige mice (B6 nubq; no T cell, no NK activity) were used as recipients for the adoptive transfer of thymocytes from B6 gld mice (generalized lymphoproliferative disease) which are a model of systemic lupus erythematous. The [gld----nubg] chimeras showed several similarities with gld control mice including the T cell disorders (lymphoproliferation and Con A-response deficiency of splenocytes) and B cell disorders (hyperglobulinemia and elevated anti-single-stranded DNA antibody titers). This suggests that the gld lymphoproliferative disorder has a thymic origin (and does not result from an abnormally extrathymic T cell development) and that the gld T cells have an essential role for the emergence of the disorders of both the T and B cells.

Aging↗
PubMed1984

The nonessential role of a humoral antibody response in acute rat cardiac allograft rejection. An ultrastructural tracer study in an adoptive transfer model.

Progressive microvascular endothelial damage is a characteristic feature of fulminant acute cardiac allograft rejection in the rat. Serial ultrastructural tracer studies using i.v. administered colloidal carbon and horseradish peroxidase have been performed in an adoptive transfer model to determine the role of cellular and humoral immune mechanisms in the pathogenesis of endothelial injury in this setting. Sublethally irradiated (780 rads) Lewis recipients of Wistar-Furth cardiac allografts reconstituted with unfractionated syngeneic immune spleen cells (2 X 10(7)] or with inocula depleted of SIg+ cells (1 X 10(7)] were studied at days 5-7 posttransplantation, and the ultrastructural tracer data were correlated with recipient alloantibody titers. The progression of microcirculatory endothelial damage within rejecting cardiac allografts was similar when recipients were reconstituted with unfractionated immune spleen cells or with SIg- cells, and the serial changes present were comparable to those documented in unmodified first-set rejection in this strain combination. Unreconstituted controls showed no apparent microvascular alterations. A significant alloantibody response was confined to recipients reconstituted with unfractionated immune spleen cells. All unreconstituted recipients and recipients that received splenic inocula depleted of SIg+ cells (SIg-) lacked detectable antibody in the study period. These results indicate that a humoral antibody response is not essential for induction of endothelial damage in fulminant acute rejection of rat cardiac allografts.

Acute Disease↗
PubMed1994

Adoptive transfer of lymphokine-activated killer cells loaded with 4'-deoxy-4'-iododoxorubicin: therapeutic effect in mice bearing lung metastases.

We studied the potential use of lymphokine-activated killer (LAK) cells loaded with 4'-deoxy-4'-iododoxorubicin (IDX) in adoptive immunotherapy experiments. Because LAK cells preferentially locate in the lung, we evaluated the therapeutic effect of IDX-loaded LAK cells in mice bearing lung metastases induced by B16F1 tumor cell injection. In vitro studies showed that LAK cells rapidly incorporated IDX, with maximum uptake at 15 min, followed by a plateau; drug efflux was initially rapid and then continued at a much slower rate. Evaluation of LAK cell cytotoxic activity against relevant target cells showed a 30% decrease after IDX treatment that progressed with time over the next 6 h. P388 tumor cell growth was inhibited by coculture with IDX-loaded LAK cells, thus demonstrating that the released IDX maintained its pharmacological activity. Finally, high performance liquid chromatography analysis of tissue IDX concentration revealed a considerably higher and long-lasting concentration in the lungs of mice receiving IDX-loaded LAK cells, compared to mice given injections of a comparable amount of free drug. Moreover, adoptive transfer of IDX-loaded LAK cells into tumor-bearing mice caused a significant reduction in the number of lung metastases versus control mice given injections of even higher doses of free drug.

Animals↗
PubMed1988

NOD marrow stem cells adoptively transfer diabetes to resistant (NOD x NON)F1 mice.

Autoimmune beta-cell destruction occurred in otherwise diabetes-resistant F1 mice from an outcross between the nonobese diabetic (NOD) and nonobese normal (NON) inbred strains after adoptive transfer of hematopoietic stem cells from NOD donors. F1 mice were lethally irradiated and reconstituted with either NOD, NON, or F1 bone marrow. Only F1 mice reconstituted with NOD bone marrow developed hyperglycemia. The long (greater than or equal to 16-wk) prodromal period required for expression of overt diabetes contrasted with the rapidity (4-6 days) with which kidney-grafted F1 or NON islets (but not anterior pituitary) were eliminated from diabetic F1 mice. Thus, development of beta-cell-specific immunologic effectors was a chronic process, but once sufficient levels of autoimmunity were achieved, implanted beta-cells could be eliminated in an acute fashion. Thus, expression of NOD diabetogenic alleles in hematopoietic progenitor cells is sufficient for development of anti-beta-cell immunity. The elimination of grafted NON islets shows the effectors are capable of eliminating beta-cells from mice without the diabetogenic genotype.

Animals↗
PubMed2005

Fate and function of anti-CD3/CD28-activated T cells following adoptive transfer: IL-2 promotes development of anti-tumor memory T cells in vivo.

BACKGROUND: Adoptive immunotherapy with T cells activated through CD3 alone requires exogenous IL-2 for T-cell function and survival after transfer, but the in vivo cytokine requirement of T cells activated through CD3 and CD28 is unknown. We hypothesized that CD3/CD28-activated T cells, unlike those activated through CD3 alone, might develop into long-lived memory T cells, either with or without systemic IL-2. METHODS: We used MHC class I-restricted TCR transgenic T cells from the OT-1 mouse, specific for the surrogate tumor Ag ovalbumin (OVA), to assess the trafficking kinetics, antigenic responsiveness and anti-tumor efficacy of dual-activated T cells in vivo as a function of IL-2 administration. At days 7, 14, and 28 after transfer, lymph node cells and splenocytes were examined for donor cell persistence and antigenic responsiveness by FACS and ELISA, respectively. RESULTS: In IL-2-treated mice, donor CD8+ T cells persisted and developed a memory phenotype, based on CD44 and Ly6c expression at day 28, while mice given no IL-2 had fewer donor cells at all time points. OVA-specific release of IFN-gamma was higher from lymphocytes of IL-2-treated mice compared with no-IL-2 mice (P<0.02 at all time points). In mice challenged with an OVA-bearing subline of the AML leukemia model C1498, IL-2 did not confer added protection from tumor challenge at 1 or 2 weeks after adoptive transfer, but gave improved survival at 4 weeks post-transfer. DISCUSSION: We conclude that exogenous IL-2 is not required for anti-tumor activity of CD3/CD28-activated CD8+ cells early after adoptive transfer, but promotes T-cell persistence that confers disease protection at more remote times.

Acute Disease↗
PubMed1996

Adoptive transfer of experimental allergic encephalomyelitis after in vitro treatment with recombinant murine interleukin-12. Preferential expansion of interferon-gamma-producing cells and increased expression of macrophage-associated inducible nitric oxide synthase as immunomodulatory mechanisms.

In an adoptive transfer model of experimental allergic encephalomyelitis, stimulation of lymph node cells with proteolipid protein and recombinant murine interleukin (rmIL)-12 before cell transfer accelerated the onset and exacerbates clinical disease. In vitro stimulation with proteolipid protein in the presence of rmIL-12 was associated with an increase in interferon-gamma-producing cells and a decrease in IL-4-producing cells, indicating a preferential expansion of Th1 effector cells. This was supported by the finding that severe disease with rapid onset could be transferred with as few as 10 x 10(6) rmIL-12-stimulated lymph node cells. Immunohistochemical analysis confirmed that the accelerated onset of disease after in vitro stimulation with rmIL-12 coincided with an acute inflammatory response in the central nervous system. At peak disease, both control and rmIL-12 treatment groups exhibited extensive cellular infiltration with characteristic perivascular cuffing. No notable differences in either the cellular composition or cytokine expression within the lesions were seen between groups. However, the frequency of macrophages that stained positively for inducible nitric oxide synthase was increased in animals challenged with rmIL-12-treated lymph node cells. The results suggest that, in addition to promoting the preferential expansion of interferon-gamma-producing cells by rmIL-12 in vitro, secondary in vivo effects leading to macrophage activation and inducible nitric oxide synthase expression may contribute to the severe and protracted course of central nervous system inflammation in this model.

Animals↗
PubMed1991

Vaccination of Lewis rats with temperature-sensitive mutants of Mycoplasma pulmonis: adoptive transfer of immunity by spleen cells but not by sera.

Temperature-sensitive mutant vaccines protect rats against Mycoplasma pulmonis infection. The role of the humoral or cellular immune response in resistance to mycoplasma infection was investigated by adoptive-transfer experiments. Spleen cells from Lewis rats vaccinated but not challenged with wild-type organisms (vaccinated) and spleen cells from rats vaccinated (or not) and challenged were effective in preventing syngeneic recipients from developing respiratory disease. There was also a significant reduction in the incidence and number of challenging organisms in the respiratory system. In contrast, sera from the same donors had no detectable effect on the number of mycoplasmas recovered or on lesion development in the respiratory tract. We conclude that cellular immunity rather than humoral immunity generated in vaccinated rats confers protection against subsequent infection.

Animals↗
PubMed1981

Eradication of disseminated murine leukemia by chemoimmunotherapy with cyclophosphamide and adoptively transferred immune syngeneic Lyt-1+2- lymphocytes.

The phenotype of T cells therapeutically effective in immunotherapy of advanced Friend virus-induced (FBL) leukemia in vivo and cytotoxic to FBL in vitro was determined. Mice bearing disseminated FBL leukemia were successfully treated by a combination of cyclophosphamide and adoptive transfer of syngeneic immune lymphocytes. Therapeutic efficacy was largely dependent on the presence of Lyt-1+2- T cells in the transferred cells, whereas cells cytotoxic to FBL tumor in vitro were derived from the Lyt-1+2+ and Lyt-1-2+ subsets. Thus, the predominate cell required to eradicate tumor in adoptive chemoimmunotherapy was not cytolytic to tumor in vitro. Potentially, the Lyt-1+2- cell may operate in vivo as an amplifier cell rather than by a direct anti-tumor effect. Elimination of the Lyt-1+ population with alpha-Lyt-1 and complement prevented the generation of significant cytotoxic responses during both primary in vitro sensitization to alloantigens and in vitro sensitization of tumour-primed cells. The capacity of Lyt-1+ cell-depleted population to generate cytotoxic responses was partially reconstituted by addition, at the initiation of culture, of interluekin 2, a T cell growth factor derived from Lyt-1+2- cells, which contain the CTL and CTL precursors, were nearly as effective in vitro as unseparated immune cells. If the remaining effector cells (i.e., Lyt-1+2- T cells) function in vivo predominantly as amplifier cells, than the tumour-bearing host must be capable of making a positive contribution to the outcome of therapy.

Animals↗
PubMed1975

Blocking antigen-antibody complexes on the T-lymphocyte activation during in vitro incubation before adoptive transfer.

Following appropriate immunization of mice with CGG or DNP-CGG spleen cells release antigen upon incubation in vitro. The release can be detected either by 'self-stimulation' of the primed cell population, so that upon adoptive transfer antibodies to CGG and DNP are produced without need for further administration of antigen, or by stimulation of indicator (primed) cells. Boosting mice with antigen in saline following initial immunization with antigen in adjuvant proves the most effective method of loading spleen cells with antigen. A small fraction (10- minus 4- minus 10- minus 5) of the antigen used for boost is retained. The antigen appears to be held on the cell surfaces in the form of antigen-antibody complexes, for it is retained on the cells for up to 13 weeks in the presence of circulating antibody, during which time its capacity to self-stimulate can be inhibited by host serum in vitro. Activated thymus cells take up detectable amounts of antigen-antibody complexes. Complexes obtained by immunization with antigen in adjuvant can be inactivated by trypsinizing spleen cells. Trypsinization of separated T and B cells reveals detectable amounts of complex on the T cells, Complexes detected on T cells in this way are believed to be equivalent to the blocking complexes operative in transplantation and tumour immunity.

Adjuvants, Immunologic↗