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We have generated mice lacking the gene for beta interferon and report that they are highly susceptible to vaccinia virus infection. Furthermore, in cultured embryo fibroblasts, viral induction of alpha interferon and of 2-5A synthetase genes is impaired. We also show that beta interferon does not prime its own expression.

Signals derived from antigen-presenting cells (APC) influence the functional differentiation of CD4(+) T cells. We report here that Serrate1 (Jagged1), a ligand for the Notch1 receptor, may contribute to the differentiation of peripheral CD4(+) T cells into either helper or regulatory cells. Our findings demonstrate that antigen presented by murine APC overexpressing human Serrate1 induces naive peripheral CD4(+) T cells to become regulatory cells. These cells can inhibit primary and secondary immune responses, and transfer antigen-specific tolerance to recipient mice. Our results show that Notch signalling may help explain 'linked' suppression in peripheral tolerance, whereby tolerance induced to one epitope encompasses all epitopes on that antigen during the course of an immune response.

It has been previously demonstrated that hybrid Ty virus-like particles (VLP) prime effective CD8(+) and CD4(+) T cell responses. In this study, we investigated the effect of treating mice with Ty VLP carrying the immunodominant epitope of Der p 1 after sensitizing them to the group 1 allergen of the house dust mite Dermatophagoides pteronyssinus (Der p 1), under conditions that induce T(h)2 immunity. We show that i.p. treatment with the hybrid VLP abrogated allergen-specific IL-5 production and reduced allergen-specific cell proliferation. This suppression of the response was mediated by CD4(+) T cells and was not accompanied by an increase in IFN-gamma production.

The systemic cytokine response to major surgical trauma was studied in 20 patients undergoing elective aortic surgery and five patients after inguinal hernia repair. Tumour necrosis factor alpha and interferon gamma were not detected in these patients. An early and short-lived interleukin 1 beta (IL-1β) response to major surgery was detected only by intensive sampling in the perioperative period. The IL-1β peak preceded a more marked interleukin 6 (IL-6) response that peaked 4–48 h after surgery. IL-6 levels had fallen sharply by 48–72 h in all patients who had an uneventful postoperative course. The IL-6 peaks were significantly lower after hernia surgery than after major aortic operations (P< 0.001); IL-1β was not detected in any samples. Three patients undergoing aortic surgery developed unexpected major postoperative complications. IL-6 levels in this group were significantly higher than those of the other patients undergoing aortic surgery within 6–8 h of skin incision, and remained elevated for longer. These rises in plasma IL-6 levels preceded the clinical onset of major complications by 12–48 h. The systemic IL-1β and IL-6 response to surgical trauma increased with the severity of the surgical insult. An early, exaggerated IL-6 response was associated with the subsequent clinical development of major complications.

Preoperative, donor-specific blood transfusion leads to indefinite survival of rat renal allografts in the strain combinations used. 51Cr-release assays have shown that the level of specific cytotoxic effector activity in the grafts of transfused (nonrejected kidney) animals is very high and may equal or exceed that seen in the grafts of untreated (rejected kidney) recipients. Such cytotoxicity demonstrates specificity for the alloantigens of the kidney, is T cell-mediated, and may persist within the transplant.

The specificity of rejection of isolated pancreatic islets was examined in the rat using a quantitative model in which syngeneic (DA) or a mixture of syngeneic and allogeneic (DA and LEW or PVG) islets were implanted beneath the capsule of the kidney of nondiabetic normal rats (DA). 3 wk after transplantation total insulin extraction assays of the kidney with its islet implant together with immunohistological examination of the site of transplantation for evidence of syngeneic or allogeneic tissue demonstrated the total destruction of allogeneic islets without any evidence of damage to syngeneic islets either distant or in immediate proximity to allogeneic islets. Pancreatic islets, and especially beta cells, appear to be particularly vulnerable to the effector arm of both autoimmune and alloimmune responses, a vulnerability that has been attributed to the cytotoxic effects of lymphokines, notably IL-1, released in both autoimmune and alloimmune responses. The experiments reported here demonstrate not only the exquisite specificity of the allograft reaction but are not compatible with a hypothesis that B cells within an intact islet are nonspecifically susceptible to destruction by lymphokines.

We studied the potential immunoenhancing effects of high doses of rIL-2 on murine T and B cell functions in vivo. Injection of rIL-2 caused a threefold or more increase in the frequencies of antigen-specific proliferative T cells, suggesting that rIL-2 initiated a polyclonal T cell response. In primary and secondary humoral immune responses, administration of rIL-2 in vivo selectively enhanced the production of IgM antibodies, whereas the IgG response was unaffected. Coadministration of rIL-2 with antigen failed to induce an isotype switch from IgM to IgG in genetically low-responding mice. Interestingly, in mice treated with rIL-2 alone (in the absence of exogenous antigen), polyclonal IgM production was induced. Polyclonal IgM production of lesser magnitude was found when mice were immunized with specific antigen in the absence of exogenous rIL-2, suggesting that local IL-2 concentrations in a primary immune response might be sufficient to elicit a polyclonal IgM response.

Cytokine gene transcription has been analyzed by direct analysis of RNA obtained from mouse heterotopic cardiac transplants. The level of expression of the cytokine genes was assessed using semiquantitative polymerase chain reaction (PCR). Expression of the cytokines investigated fell into three groups. The first group included interleukin 1 beta (IL-1 beta), IL-5, IL-6, and interferon gamma (IFN gamma). These genes were expressed in normal heart tissue at low level and were upregulated following both syngeneic and allogeneic transplantation. Genes in the second group (IL-1 alpha, IL-3) were not expressed at detectable levels in normal heart but were induced following either syngeneic or allogeneic heart grafting. IL-2, IL-4, and tumor necrosis factor beta (IFN beta) comprised the third group and these cytokines were expressed only in allogeneic grafts after transplantation.

Despite considerable evidence documenting the central nervous system as a site of immunological privilege, immune responses do occur within the brain and neural allografts between major histocompatibility complexes (MHC) and minor antigen incompatible rat strains may be rejected. The survival of completely MHC incompatible neural allografts has been found to be prolonged indefinitely after administration of a monoclonal antibody (mAb) to the interleukin 2 receptor (IL-2R) for 10 d after transplantation. Here we present evidence that rats with long-term surviving lateral ventricular neural allografts, after anti-IL-2R treatment, accept subsequent neural allografts from the same donor strain, placed in a peripheral nonprivileged site, but rapidly reject third-party grafts. Thus, treatment with a mAb to the p55 chain of the IL-2R has resulted in the specific acceptance of second grafts of fully allogeneic neural tissue. These results suggest that ongoing interaction between elements of the host immune system and alloantigen within the brain maintains the tolerant state and furthermore, that interruption of signaling through the IL-2R may be important in allospecific tolerance induction.

Tolerance to alloantigen may be induced in rats by administration of blood followed by transplantation of a renal allograft. The mechanism of this tolerance was investigated by directly analyzing the functional activity of graft-infiltrating cells. We have previously shown cytotoxic T lymphocyte infiltration of, and major histocompatibility complex induction on, grafts of tolerant animals. We now report that cells isolated from the grafts of tolerant rats show a reduced expression of the p55 interleukin 2 receptor (IL-2R) chain on the cell surface compared with that seen on the cells of untreated animals. Scatchard analysis further reveals low expression of high affinity IL-2R. This is due to reduced transcription of both IL-2R alpha and beta chain mRNAs and results in a reduced ability of cells to proliferate in response to IL-2. Cells isolated from tolerant animals are unable to make biologically active IL-2 in culture, whereas cells from untreated animals make high levels. This is not reflected at the mRNA level as the IL-2 gene is induced in both tolerant and untreated animals to similar levels. The induction of tolerance is abrogated by administration of recombinant IL-2 to animals at the time of transplantation. Thus, we conclude that an altered regulation of the IL-2 pathway results in tolerance in these alloantigen-treated and transplanted animals.