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PubMed1986

Adoptive transfer of immunity against virulent Semliki Forest virus with immune spleen cells from mice infected with avirulent Semliki Forest virus.

This paper describes the minimal requirements to protect mice adoptively against challenge with virulent Semliki Forest virus (SFV). Early immune serum, from donor mice infected with an avirulent strain of SFV, contained mainly neutralizing IgM immunoglobulins. More of these antibodies (1.80 PND50 vs 0.06 PND50) were needed to protect recipient mice against intraperitoneal challenge (10 LD50 of SFV) than against subcutaneous challenge (7 LD50). Adoptive transfer experiments indicated that a minimum of 3 X 10(7) six-day immune spleen cells were also able to protect recipient mice against intraperitoneal challenge with 10 LD50 of SFV. Treatment of these donor cells with cytotoxic antisera and complement revealed both T- and B-lymphocytes were required for optimum adoptive immunity. Surviving recipients of either immune serum or immune spleen cells developed significantly less neutralizing antibodies than control mice. The lower antibody titres in protected mice might be related to either immune serum or immune spleen cell mediated restriction of virus replication; meaning a reduced antigenic stimulus in these mice compared to control mice.

Animals↗
PubMed1985

Migration of radiolabeled, adoptively transferred T-lymphocytes into the mammary gland and milk of lactating rats.

The maternal component in the transfer of cellular immunity from the mother to the neonate during lactation was investigated by analyzing the migration of adoptively transferred T-lymphocytes to the mammary gland and into the milk of lactating rats. A T-enriched cell population, containing less than 2.5% of contaminating B-cells, was obtained from mesenteric and peripheral lymph node cells of donor rats by removing B-cells with a panning technique. The T-enriched cells, radiolabeled with [3H]uridine, were injected intravenously into syngeneic lactating females, between 1 and 4 days post-partum. Samples of mesenteric and cervical lymph nodes, spleen, Peyer's patches, small intestine, and mammary gland taken at 48 h and milk obtained at 24 and 48 h were processed for scintillation counting and autoradiography. A large portion of the injected T-cells migrated to T-dependent lymphoid areas (the paracortical and medullary regions of the mesenteric and cervical lymph nodes and the Peyer's patches) and a substantial number also migrated into the small intestine and mammary gland, although the frequency of cells per high-power field was lower than in the lymph nodes. However, total counts of activity recovered were significantly higher in the small intestine and mammary gland than in either the mesenteric or cervical groups of lymph nodes. The distribution of the T-cells within the mammary gland showed a relative predominance of labeled cells in the connective tissue adjacent to the alveolar secretory cells, with a small percentage of cells present within the mammary epithelium. The direct transfer of T-cells through the alveolar epithelium was demonstrated by the presence of labeled cells in milk. These results substantiate that a significant number of T-lymphocytes migrate not only to the mammary gland during lactation but also into milk. These cells may play a passive regulatory or inductive role within the mammary gland or an active role in the maternal-to-neonatal transfer of immunity.

Animals↗
PubMed1979

Adoptive transfer of experimental allergic encephalomyelitis: incubation of rat spleen cells with specific antigen.

Spleen cells from myelin basic protein (BP)-sensitized donor rats appear to be incapable of adoptively transferring experimental allergic encephalomyelitis (EAE) directly to normal recipients. It has been reported that in vitro incubation with concanavalin A (Con A) activates rat spleen cells so that they are capable of transferring EAE. We report here that incubation with specific antigen, BP, also permits transfer of disease with spleen cells. Data are presented in which activation of EAE spleen cells by Con A is compared with activation by BP. Cellular proliferation does not appear to be necessary for in vitro activation with specific antigen.

Animals↗
PubMed1993

Cell-mediated antiviral response to equine herpesvirus type 1 demonstrated in a murine infection model by means of adoptive transfer of immune cells.

Protection against equine herpesvirus type 1 (EHV-1) infection in a mouse model has been studied by means of delayed-type hypersensitivity (DTH) and adoptive transfer of immune spleen cells. Mice were found to develop a positive DTH response to EHV-1 antigen which was sustained for several months after primary inoculation. The response was found to cross-react with EHV-4-derived antigen. Immune cells (from mice primed with live or heat-inactivated EHV-1) conferred an enhanced DTH response on recipients; however, only the immune cells that were previously primed with live EHV-1 gave protection against re-infection. The degree of protection was also dependent on the number of spleen cells transferred. Immune cells from mice primed with heat-inactivated EHV-1 appeared to enhance virus replication following subsequent inoculation. The serum antibody response to EHV-1 appeared to be slightly suppressed in recipients of spleen cells from mice primed with either live or heat-inactivated virus. These results support the important role for cell-mediated responses in protective immunity to EHV-1 and provide clues to the nature of protection and immunopathology in the natural host.

Animals↗
PubMed2005

Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells.

Depletion of immune elements before adoptive cell transfer (ACT) can dramatically improve the antitumor efficacy of transferred CD8+ T cells, but the specific mechanisms that contribute to this enhanced immunity remain poorly defined. Elimination of CD4+CD25+ regulatory T (T reg) cells has been proposed as a key mechanism by which lymphodepletion augments ACT-based immunotherapy. We found that even in the genetic absence of T reg cells, a nonmyeloablative regimen substantially augmented CD8+ T cell reactivity to self-tissue and tumor. Surprisingly, enhanced antitumor efficacy and autoimmunity was caused by increased function rather than increased numbers of tumor-reactive T cells, as would be expected by homeostatic mechanisms. The gammaC cytokines IL-7 and IL-15 were required for augmenting T cell functionality and antitumor activity. Removal of gammaC cytokine-responsive endogenous cells using antibody or genetic means resulted in the enhanced antitumor responses similar to those seen after nonmyeloablative conditioning. These data indicate that lymphodepletion removes endogenous cellular elements that act as sinks for cytokines that are capable of augmenting the activity of self/tumor-reactive CD8+ T cells. Thus, the restricted availability of homeostatic cytokines can be a contributing factor to peripheral tolerance, as well as a limiting resource for the effectiveness of tumor-specific T cells.

Adoptive Transfer↗
PubMed1991

Hymenolepis nana: adoptive transfer of protective immunity and delayed type hypersensitivity response with mesenteric lymph node cells in mice.

A marked degree of footpad swelling was observed in BALB/c mice infected with Hymenolepis nana eggs, when soluble egg antigen was injected into their footpads 4 to 21 days after the egg infection, indicating delayed type hypersensitivity responses in infected mice. Adoptive transfer with mesenteric lymph node cells from donor mice (BALB/c strain; +/+) infected with eggs 4 days before cell collection could confer this hypersensitivity to recipient nude mice (BALB/c strain; nu/nu). These mesenteric lymph node cells were then divided into two fractions, blast-enriched and blast-depleted cells, by density gradient centrifugation with Percoll. The recipients intravenously injected with the blast-depleted cell fraction showed a marked increase in footpad thickness, whereas the intravenous transfer of the blast-enriched cell fraction resulted in an insignificant increase in footpad thickness. The transfer of the blast-enriched cell fraction, but not of the blast-depleted cell fraction, conferred a strong adoptive immunity on syngeneic recipient nude mice, when the immunity transferred was assessed by examining cysticercoids developed in the intestinal villi on Day 4 of challenge infection. The lack of delayed type hypersensitivity response in mice that received the blast-enriched cell population was not due to a lack of the capacity of the cells to induce the response, because the cells were capable of inducing a significant increase in thickness of footpads of normal mice when these cells were locally injected into the footpad together with soluble egg antigen.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1982

Short lived, dividing cells mediate adoptive transfer of immunity to Trichinella spiralis in mice. II. In vivo characteristics of the cells.

The in vivo characteristics of mesenteric lymph node cells (MLNC) capable of mediating the adoptive transfer of immunity to Trichinella spiralis have been examined. Mediator cells were diverted into the peritoneal cavity of infected donor mice following the induction of a peritoneal exudate and its was shown that these were nylon-wool, non-adherent (T) cells. After density gradient separation of [125I]-UdR-labelled MLNC, the fractions that were most effective in transferring immunity were those containing a small proportion of cells but the largest proportion of incorporated activity. Treatment of the donors of MLNC with the mitotic inhibitor vinblastine effectively prevented both the transfer of immunity and increased incorporation of [125I]-UdR characteristic of the mediator population. In vitro irradiation of MLNC failed to affect their ability to transfer immunity. Collectively these findings support the conclusion that mediator cells are T lymphoblasts, and suggest that mediation of immunity is effected directly by this population and not by their progeny.

Animals↗
PubMed1995

Adoptive transfer of bryostatin-activated tumor-sensitized lymphocytes prevents or destroys tumor metastases without expansion in vitro.

Because the requirement for long-term cell culture can make adoptive cellular immunotherapy cumbersome, experiments were designed to determine whether smaller numbers of tumor-sensitized T cells activated briefly with bryostatin 1 and ionomycin (B/I) could be returned immediately to recipient mice without in vitro expansion and still have an anti-tumor effect in vivo. Popliteal tumor-draining lymph nodes (DLNs) from mice bearing progressive MCA-105 and MCA-203 footpad sarcomas were harvested and treated for 18 h with B/I. These cells were then washed and transferred immediately to naive C57B1/6 mice. In some experiments, these mice were irradiated (500 rads) before adoptive transfer and were given interleukin-2 (IL-2, 7,500 IU i.p., b.i.d. for 3 days) after receiving the activated lymphocytes. Recipient mice were challenged with sarcoma cells (4 x 10(5) i.v.) 6 to 32 days after receiving the activated lymphocytes. Mice receiving 10(6) B/I-activated lymphocytes before tumor challenge had significantly fewer metastases than did controls. This protective effect did not require exogenous IL-2 or host irradiation. Using Thy-1 congenic donors, it was shown that B/I-activated T cells expanded in recipients when IL-2 was also given, and these cells were a prominent component (15% of total cells) in the infiltrates found in the lungs of mice 7 days after i.v. tumor challenge. Combining these B/I-"pulsed" cells with cyclophosphamide (CYP) and IL-2 to treat mice with established (3-day) metastases resulted in significant reduction in pulmonary nodules, with complete regression in many of the treated mice, which was rarely seen with CYP alone or with CYP + IL-2. Thus, adoptive transfer of tumor-sensitized, B/I-activated DLN cells confers protection against i.v. tumor challenge, without prior in vitro expansion of the effector cells. Phenotyping studies demonstrate that donor cells activated with B/I do expand in recipient mice after adoptive transfer and can move to sites of tumor. Moreover, these cells can mediate a therapeutic effect on established tumor metastases, when combined with chemotherapy.

Adjuvants, Immunologic↗
PubMed1989

Tumor localization of adoptively transferred indium-111 labeled tumor infiltrating lymphocytes in patients with metastatic melanoma.

Lymphoid cells infiltrating into human tumors can be expanded in vitro in medium containing interleukin-2 (IL-2). Adoptive transfer of these tumor-infiltrating lymphocytes (TIL) mediates potent antitumor effects in murine tumor models. Clinical trials to evaluate the efficacy of these cells in patients with advanced cancer are underway. We have investigated whether infused TIL labeled with indium 111 (111In) oxine can traffic and localize to metastatic deposits of tumor. Six patients with metastatic malignant melanoma who had multiple sites of subcutaneous, nodal, and/or visceral disease were the subjects of the study. The patients received cyclophosphamide 36 hours before receiving the intravenous (IV) infusion of TIL followed by IL-2 IV every eight hours. The distribution and localization of the TIL were evaluated using serial whole body gamma camera imaging, serial blood and urine samplings, and serial biopsies of tumor and normal tissue. 111In-labeled TIL localized to lung, liver, and spleen within two hours after the infusion of activity. Activity in the lung diminished within 24 hours. As early as 24 hours after injection of 111In-labeled TIL, localization of TIL to sites of metastatic deposits was demonstrated in all six patients using either imaging studies or biopsy specimens or both. 111In activity in tumor tissue biopsies ranged from three to 40 times greater than activity in normal tissue. A progressive increase in the radioactive counts at sites of tumor deposit was seen. This study shows that labeled TIL can localize preferentially to tumor, and provides information concerning the possible mechanism of the therapeutic effects of TIL.

Adult↗
PubMed1978

Parainfluenza 1 (6/94) virus-induced white matter degeneration: enhancement by adoptive transfer of virus-sensitized immunocytes.

Intracerebral (i.c.) inoculation of parainfluenza 1 (6/94) virus into weanling Lewis rats produced meningitis, choroiditis, ependymitis, and a rare noninflammatory white matter degeneration (WMD). Adoptive transfer of immune spleen cells (ISC), 3 to 5 days after virus infection, significantly increased the incidence of WMD. Conversely ISC given 2 days prior to virus infection not only protected rats from developing WMD, but also from developing meningitis, choroiditis, or ependymitis. Thus the temporal relationship of 6/94 virus inoculation to the virus-specific immune response appears critical in determining whether WMD will develop in association with 6/94 virus infection. Although sensitized immunocytes may prevent pathologic changes if given prior to virus inoculation, such immunocytes enhance the production of WMD if given after such inoculation. These studies underline the dual role of the immune response in 6/94 virus infection, and indicate that 6/94 virus-induced WMD is, in part, immunemediated.

Animals↗
PubMed1988

Adoptively transferred experimental autoimmune encephalomyelitis in SJL/J, PL/J, and (SJL/J x PL/J)F1 mice. Influence of I-A haplotype on encephalitogenic epitope of myelin basic protein.

Guinea pig basic protein (GPBP)-immune lymph node cells (LNC) from SJL, PL, and SJL x PL (F1) mice proliferated to whole GPBP and GPBP fragments 1-37, 43-88, and 89-169. All three strains of mice developed experimental allergic encephalomyelitis (EAE) by active immunization with whole GPBP or by passive transfer of LNC cultured with whole GPBP. SJL (H-2s) and PL (H-2u) mice developed EAE by active immunization with fragments 89-169 or 1-37, respectively, or by passive transfer of LNC cultured with the same Ag. F1 mice developed EAE by active immunization only with fragment 1-37 or by passive transfer of LNC cultured with either of the above fragments. Removal of macrophages (MO) from immune-F1 LNC resulted in the loss of a proliferative response and the ability to transfer EAE. Reconstitution of MO-depleted immune F1 T cells with either F1-, SJL-, or PL-MO restored the proliferative responses to whole GPBP and the three fragments. Cultures of immune F1 T cells reconstituted with any of the three MO populations and incubated with whole GPBP passively transferred EAE into naive F1 mice. Immune F1 T cells cultured with F1 MO in the presence of either fragment 1-37 or 89-169 transferred EAE. F1 T cells cultured with SJL MO were able to transfer EAE only if the Ag was fragment 89-169, whereas F1 T cells cultured with PL MO were able to transfer disease only if incubated in the presence of fragment 1-37. F1 mice are passively susceptible to EAE induced by adoptive transfer of cells reactive to either the N-terminal or C-terminal fragment and that the encephalitogenic determinant of GPBP is related to the genome of MO present in vitro.

Animals↗
PubMed1979

Adoptive transfer of immunity and suppression by cells and serum in early Mycobacterium lepraemurium infections of mice.

The ability of lymphocytes and serum from mice infected with 10(7) Mycobacterium lepraemurium to adoptively transfer resistance to irradiated (600 rad 60 cobalt) syngeneic mice was studied. Two strains of mice were used: BALB/c mice, which are highly susceptible to moderate cutaneous infections with M. lepraemurium, and C57Bl mice, which are comparatively resistant. In both strains of mice recipients of nylon wool non-adherent spleen cells, and thus T lymphocyte recipients, demonstrated increased resistance to subcutaneous infection with 10(7) M. lepraemurium. Significantly increased susceptibility to infection was noted in the BALB/c recipients of nylon wool adherent spleen cells or serum. No suppressor activity could be demonstrated in the resistant C57Bl strain.

Animals↗
PubMed1990

Synergistic interaction between immune serum and thoracic duct cells in the adoptive transfer of rapid expulsion of Trichinella spiralis in adult rats.

Rapid expulsion of Trichinella spiralis could be transferred to naive adult rats with thoracic duct lymphocytes and immune serum. Thoracic duct cells collected from Days 3-5 and immune serum collected on Day 28, respectively, after infection were effective. Both cells and serum were unable to transfer rapid expulsion when given alone, even in large volumes. Recipients of immune serum and cells eliminated a significantly higher number of larvae than control rats by 1 hr after challenge with muscle larvae. Rapid expulsion produced 30-80% larval worm rejection but could not be increased by the transfer of more cells or immune serum. Mucus trappings did not appear to play a role in the rejection process. After transfer of 2 x 10(8) cells and 4.0 ml immune serum, rapid expulsion persisted for less than 1 week. However, after adoptive transfer of cells alone, the gut remained functionally receptive to the passive transfer of immune serum for 7 weeks. Therefore, the changes effected by transfer of cells were long lived in contrast to the 1 week, or less, of functional persistence by transferred immune serum. The data indicate that two separate processes, one cell mediated and the other immune serum mediated, interact synergistically in the intestine and lead to the expression of rapid expulsion.

Animals↗
PubMed1996

In vivo MRI and its histological correlates in acute adoptive transfer experimental allergic encephalomyelitis. Quantification of inflammation and oedema.

In vivo proton MRI was carried out on a 7 Tesla system at 2-3 day intervals over 10 days in rats with adoptive transfer experimental allergic encephalomyelitis (AT-EAE), an animal model of some aspects of multiple sclerosis. In order to assess the integrity of the blood-brain barrier (BBB), MRI was performed by acquiring quantitative MR-relaxation time T1 images of the AT-EAE rat brain before and after i.v. injection gadolinium-diethylene triaminepentaacetic acid (Gd-DTPA) using an ultrafast MRI technique. The MRI findings were compared with the immunohistochemical stain of T cells, macrophages and albumin and, in addition, apoptosis of T cells was assessed using in situ nick translation (ISNT). Prior to injection of Gd-DTPA, an increase of T1 times in the brain of the AT-EAE rats was observed, which paralleled the time course of albumin in histological sections. These were MRI findings observed well before the onset of major cellular infiltration and before the onset of clinical signs. After i.v. injection of Gd-DTPA the observed decrease of T1 times paralleled macrophage activation, and less closely T-cell infiltration. Our results provide evidence that using MRI, it is possible to assess quantitatively the breach of the BBB and to distinguish in vivo between two components of the early phase of the lesion, inflammatory infiltrates and vasogenic oedema.

Acute Disease↗
PubMed1976

Mechanism of inhibition of adoptive transfer of tuberculin sensitivity in acute uremia.

Cell-mediated immunity is reduced in uremia, but the mechanism of this inhibition is poorly understood. To determine the site of inhibition a study of adoptive transfer of cell-mediated immunity was undertaken. Strain 13 guinea pigs were made uremic by ureteral ligation. Lymph node cells were isolated and transferred in the following three ways: Group 1: tuberculin sensitive nonuremic donors to nonimmune nonuremic recipients; Group 2: tuberculin sensitive nonuremic donors to nonimmune uremic recipients; Group 3: tuberculin sensitive uremic donors to nonimmune nonuremic recipients. There was no difference in the skin test responses of the transfer recipients in Groups 1 and 3, even though the uremic donors in Group 3 had lost their skin test reactivity. Transfer of tuberculin sensitivity was not successful in Group 2. These results indicate that the uremic state inhibits previously established skin test reactivity but does not prevent sensitized T lymphocytes from transferring cellular immunity.

Acute Disease↗
PubMed1990

Protection against Leishmania major in BALB/c mice by adoptive transfer of a T cell clone recognizing a low molecular weight antigen released by promastigotes.

We have shown previously that BALB/c mice can be protected against a fatal infection with Leishmania major by adoptive transfer of a T cell line recognizing a protective soluble fraction (fraction 9) of promastigotes. We now describe the isolation and characterization of a T cell clone (9.1-2) that also transfers protective immunity against Leishmania. After Ag or mitogen stimulation, this clone secrets IL-2 and IFN-gamma, but not IL-4 or IL-5. The clone preferentially recognizes L. major fraction 9, and in addition, soluble Ag from Leishmania donovani, Leishmania amazonensis, and Leishmania braziliensis, but not from the related flagellates, Trypanosoma cruzi or Crithidia fasciculata. Besides being contained in fraction 9, the stimulatory Ag is also released from the parasite, because concentrated promastigote culture supernatants induced IFN-gamma production by 9.1-2. By means of T cell immunoblotting, we determined that 9.1-2 recognized a protein with a relative m.w. between 8,000 and 12,000, and within this region is a predominant protein contained in fraction 9 of approximately 10,000 m.w. These data identify a new candidate Ag for immunization against protozoa belonging to the genus Leishmania.

Animals↗
PubMed1978

Plasmodium berghei adoptive transfer and immunosuppression of immunity in allogenic neonates.

Outbred female rats were hyperimmunized with Plasmodium berghei and mated to produce progeny. Spleen cells from the immunized rats and from normal control mothers were adoptively transferred to their 48 hr old neonates. Some neonates from immune mothers were fostered to normal mothers and vice versa. Weanling rats were challenged 35 days after birth with Plasmodium berghei; immune and normal litters which had not received cells were also challenged at the same time. Rats which had received immune spleen cells from their mothers but were fostered on to non-immune mothers showed significantly lower parasitaemias and higher fluorescent antibody titres than any other combination of cell transfer and maternal milk. GVH reaction was minimal. These results suggest that the immune response to P. berghei was suppressed in the presence of passively transferred maternal antibody.

Animals↗