Therapeutic immunology最新文献

Several approaches have recently been put forward describing attempts to suppress the IgE immune response towards allergens, which is thought to be the key event in allergic diseases. In a series of clinical trials we have shown that injections of complexes made up from allergen and specific antibodies are an effective treatment for allergic bronchial asthma and atopic dermatitis. In the work presented here we have examined the humoral immunity changes associated with the use of such complexes in a group of 19 adult patients suffering from atopic dermatitis and hypersensitive to Dermatophagoides pteronyssinus (Dp), and in whom a significant clinical improvement was observed. By comparing serum samples taken prior to and after 4 months of therapy, we show that the administration of immune complexes is associated with: (i) a significant and selective reduction of IgG and IgE antibodies specific for Dp allergens; (ii) a down-regulation that affects only the antibodies present in the complexes; (iii) the induction of corresponding anti-idiotypic antibodies. To our knowledge, this is the first demonstration in humans that an anti-allergen antibody response can be down-regulated in a highly selective manner and that this is accompanied by significant clinical improvement. Moreover, the selective reduction of IgG antibodies could be of value in the treatment of some forms of auto-immune diseases.

We have investigated the ability of the novel muramyl dipeptide, GMDP, to act as an adjuvant for the induction of ovalbumin (OVA)-specific, CD8+ cytotoxic T lymphocyte (CTL) responses. C57Bl/6 mice were twice immunized s.c. with 50 micrograms OVA emulsified with a squalane, L121 pluronic containing Tween-80 vehicle either with (STP-GMDP) or without (STP) GMDP. Splenic precursor CD8+ CTL activity against E.G7-OVA, but not against EL-4 parental targets was detected in STP-GMDP immunized mice after 5 days of in vitro re-stimulation with irradiated E.G7-OVA cells, while mice immunized with OVA in STP alone or OVA alone failed to demonstrate CTL activity. OVA emulsified in a microfluidized STP vehicle formulation without GMDP also elicited the E.G7-OVA precursor CTL. The ability of GMDP to induce a class I-restricted, CD8+ CTL response to a soluble protein antigen may have implications for the development of useful vaccines against viral pathogens or tumours against which CTL responses are desirable.

The murine monoclonal antibody OKT3 is the best known of the anti-CD3 antibodies used for the prevention and treatment of renal allograft rejection. Use of this antibody is associated with improved graft outcome but it has a number of adverse effects thought to result from the massive release of pro-inflammatory cytokines. It has been postulated that OKT3 causes cytokine release because of cross-linking of CD3 molecules on the cell surface by bivalent anti-CD3 antibodies, such as OKT3, and the simultaneous binding of the Fc regions of these monoclonal antibodies to Fc receptors on other cells resulting in cell activation. Monovalent antibodies directed against the CD3 antigen should not, in theory, cause cell activation and cytokine release by this postulated mechanism. This study details the use of a monovalent anti-CD3 monoclonal antibody in the treatment of allograft rejection in five renal transplant recipients and documents the degree of TNF, IFN-g and IL6 release generated after antibody injection. Monovalent anti-CD3 monoclonal antibody reversed the rejection episode for which it was used and was well tolerated in all patients. TNF, IFN-g and IL6 measurement showed that little pro-inflammatory cytokine release occurred after this drug. It is likely that the relative lack of side-effects of monovalent anti-CD3 reflects the blunted release of pro-inflammatory cytokines. Monovalent anti-CD3 monoclonal antibody may be a useful addition to the reagents available to treat allograft rejection.

It has long been assumed that papilloma regression is mediated by immunological mechanisms which are probably cellular in nature. The potentiation of these responses may alter the course of papilloma progression. Certain strains of the bacterium Corynebacterium parvum (Propionibacterium acnes) have been shown to augment cellular immune mechanisms by increasing both macrophage and natural killer cell activity. This study involves the use of naturally occurring bovine papillomas to investigate the immune mechanisms involved in induced papilloma regression. Papillomas were treated by intralesional injection of a C. parvum suspension. Treated papillomas were biopsied at various stages of regression. Tissue samples were subjected to immunohistochemical staining to identify specific infiltrating cells. Results showed that intralesional administration of C. parvum was capable of inducing regression of bovine papillomas in 8-15 weeks. Immunological staining revealed that regression was associated with an increased number of CD8+ and gamma delta+ cells in the dermis, as well as a marked infiltration of neutrophils.

The feasibility of utilizing the differential permeability of the blood-tumour barrier to low- vs. high-molecular-weight compounds is demonstrated in a brain tumour model. Nude rats (n = 27) with or without intracerebral tumours received intravenous [3H]methotrexate (M(r) 454), followed 60 min later by antimethotrexate antibody (M(r) 150,000) or nonspecific mouse antibody. Antimethotrexate antibody resulted in 93% binding of serum methotrexate. In contrast, the percentage of antibody-bound methotrexate in brain and intracerebral tumour was only slightly greater than preantibody protein binding. Methotrexate delivery to tumour was significantly greater than to brain adjacent to tumour and normal brain. The percentage delivery of [3H]methotrexate to all areas of brain was similar between animals receiving antimethotrexate antibody and nonspecific antibody. These findings support the theory that a drug rescue method may be developed that may permit the safe administration of increased dosages of chemotherapeutic drugs for the treatment of intracerebral tumours.

The antiglobulin (anti-Ig) response to therapeutic monoclonal antibodies (mAbs) poses a significant obstacle to their routine application in man. Whilst humanization has lessened the problem, repeated courses of humanized mAbs still sensitise some patients. Previous work suggested that unresponsiveness to cell-binding (therapeutic) mAbs could not be achieved due to an unexpected immunogenicity of their idiotypes (ids). The current work examines this phenomenon in more detail using CBA/Ca mice receiving rat antimouse CD8 mAbs as a model system. It is shown that the anti-Ig response is dependent on CD4+ T-cells. Furthermore, for at least some mAbs, most helper epitopes appear to reside within the mAb c-region. Consequently, when tolerance is induced to c-region (isotype), the anti-id response is extremely weak (induced helplessness). For one (weakly immunogenic) CD8 mAb concomitant administration of a CD4 mAb was sufficient to induce tolerance, whereas for another (more immunogenic) CD8 mAb, tolerance could only be achieved by prior concomitant exposure to both a CD4 mAb and an isotype-matched non-cell-binding mAb. The general applicability of these results is discussed and extrapolated to the clinical situation. Non-cell-binding variants of therapeutic mAbs could be usefully exploited to generate therapeutic unresponsiveness to any clinically useful mAb.

In this paper, we examine in a murine system whether cyclophosphamide (CY) could prevent the development of fatal GVHD and furthermore whether it could be used to treat on-going GVHD. (C57BL/6xDBA/2)F1 (BDF1) mice were injected with spleen cells from B6 donors and their thoraces were opened to mimic cardiac operation. These mice lost body weight gradually and most of them died during 2-4 weeks post-transfusion. They showed splenomegaly, thymic atrophy and marked bone-marrow aplasia. When CY was administered at 100 mg kg-1 on days 0, 2, 7 and 9, all mice were relieved of GVHD and their organs were almost free of signs of GVHD. CY (100 mg kg-1) administered on days 7 and 9 also save mice from lethal GVHD. Moreover, CY administered at a dose of 20 mg kg-1 on days 9 and 11 when GVHD became apparent was also effective. These data suggest that CY might be used as a therapeutic agent for lethal post-transfusion GVHD.

Recent studies in the immunopathogenesis of bovine leukemia virus (BLV) infection in ruminants, reviewed herein, provide an insight into the vaccination strategy against retrovirus infection. It was shown that vaccination of naive sheep with a recombinant vaccinia virus (RVV) expressing BLV envelope glycoprotein protected the animals against BLV infection. The involvement of cell-mediated immunity (CMI) in this phenomenon was strongly suggested. The postinfection vaccination, that is, the vaccination of BLV-infected animals with RVV, also significantly suppressed BLV replication in the carrier animals. These findings support the idea that vaccination against retroviruses should put its emphasis on the induction of CMI and that such vaccine could be used not only for prophylactic but also for therapeutic purposes.

Recent advances which have lead to the cloning of numerous immunoglobulin genes has resulted in the production of a variety of recombinant small antibody-like molecules. These smaller immunoglobulin derived molecules have potential for the development of diagnostic and pharmaceutical compounds. The considerations in the design and production of smaller antibody-like molecules and their clinical applications will be summarized in this review.