The epidemiology of Mycobacterium bovis infections in animals and man: a review.

Tuberculosis is primarily a respiratory disease and transmission of infection within and between species is mainly by the airborne route. Mycobacterium bovis, the cause of bovine-type tuberculosis, has an exceptionally wide host range. Susceptible species include cattle, humans, non-human primates, goats, cats dogs, pigs, buffalo, badgers, possums, deer and bison.

The role of infiltrating macrophages in islet destruction and regrowth in a transgenic model.

The expression of interferon-gamma (IFN-gamma) in pancreatic beta cells leads to a complex pathology that represents the processes of both islet destruction and islet regeneration. Inflammatory cells and the factors elicited from them participate in the development of pathology in this transgenic model. To dissect the role of infiltrating macrophages in these events, the monoclonal directed against the type 3 complement receptor (5C6) was utilized to inhibit the extravasation of macrophages.

Aspartate at position 57 of nonobese diabetic I-Ag7 beta-chain diminishes the spontaneous incidence of insulin-dependent diabetes mellitus.

MHC class II genes have been shown to influence the development of the autoimmune disease insulin-dependent diabetes mellitus (IDDM) in the nonobese diabetic (NOD) mouse. In human IDDM it has been suggested that the presence of an aspartate at position 57 of the DQ beta-chain might be important in determining resistance to development of IDDM. The involvement of MHC class II genes in IDDM was investigated through the introduction of MHC encoding transgenes.

Tolerance induction as a therapeutic strategy for the control of autoimmune endocrine disease in mouse models.

This chapter aims to describe ways in which autoimmunity can be prevented or reversed and 'self-tolerance' re-established. To this end we have largely restricted our overview to the two main autoimmune disease models with which we are involved, i.e.

Non-diabetogenic insulitis in NOD<-->B10.GD allophenic mice in spite of permissive class I MHC antigens.

Allophenic mice (embryo aggregation mouse chimeras) enable us to dissect the process of spontaneous autoimmunity under physiological conditions. Our previous experiments showed that the autoimmune process in allophenic mice of the NOD<-->C57B1/6 strain combination does not progress from insulitis to diabetes. One possible explanation for this protection is that H-2 Kd-restricted CD8+ T cells kill only NOD beta cells (Kd,Db) in the chimeric islets, while the B6 beta cells (Kb,Db) are spared from destruction.

Studies on the thymus of non-obese diabetic (NOD) mice: effect of transgene expression.

The non-obese diabetic (NOD) mouse is a good model of insulin-dependent diabetes mellitus. Autoreactive T cells may play a fundamental role in disease initiation in this model, while disregulation of such cells may result from an abnormal thymic microenvironment. Diabetes is prevented in NOD mice by direct introduction of an E alpha d transgene (NOD-E) or a modified I-A beta chain of NOD origin (NOD-PRO or NOD-ASP).

The regulation of autoimmunity through CD4+ T cells.

Our experiments imply that it is possible to use monoclonal antibody therapy to reestablish self tolerance to self antigens. This can be achieved by using a short course of an nd anti-CD4 antibody thus avoiding the problem of long term immunosuppression. The mechanism by which such a state of self tolerance is achieved remains to be clarified but possible mechanisms include deletion or anergy of autoreactive T cells or some form of suppression mediated through local cytokine production.

Expression of major histocompatibility complex class I antigens at low levels in the thymus induces T cell tolerance via a non-deletional mechanism.

Transgenic CBA (H-2k haplotype) mice expressing the H-2 Kb major histocompatibility complex (MHC) class I gene under control of transcriptional promoter elements from a milk protein gene display high-level H-2 Kb transcription in lactating mammary glands and low-level transcription in skin and thymus of male and virgin female transgenic mice. However, H-2 Kb antigen could be detected only in lactating mammary gland epithelial cells by immunohistological methods. All transgenic mice are tolerant of H-2 Kb since they fail to reject skin grafts from mice expressing H-2 Kb molecules.

The use of a non-depleting anti-CD4 monoclonal antibody to re-establish tolerance to beta cells in NOD mice.

The use of immunosuppressive drugs in the management of autoimmunity penalizes a large part of the immune system for the misdemeanors of a small minority of T cells. An ideal form of therapy would be one in which it were possible to render the immune system tolerant of the inciting antigens with minimal effects on other responses. We here show that it is possible to re-establish self tolerance in an animal model of insulin-dependent diabetes mellitus without prior deletion of CD4+ T cells using a short course of therapy with a non-lytic monoclonal antibody to the CD4 adhesion receptor on T cells.

Expression and function of Qa-2 major histocompatibility complex class I molecules in transgenic mice.

Qa-2 molecules are weak transplantation antigens encoded by class I genes of the major histocompatibility complex. When expressed in transgenic CBA mice, Qa-2 molecules provoke rapid rejection of skin grafts and strong, Qa-2 specific, cytotoxic T-cell responses. Efficient rejection of skin grafts from Qa-2 transgenic mice takes place when Qa-2 molecules are attached to the cell membrane with a glycophosphatidyl anchor or by a transmembrane protein domain, except that rejection times are slightly longer in the former case.

Characterization of pancreatic islet cell infiltrates in NOD mice: effect of cell transfer and transgene expression.

Insulin-dependent diabetes mellitus can be transferred into young irradiated non-obese diabetic (NOD) mice by spleen cells from a diabetic NOD donor. T cells (both L3T4+ and Ly-2+) enter the pancreas 2 weeks following transfer. They are present initially at peri-islet locations but progressively infiltrate the islet with accompanying beta cell destruction.

Transfer of diabetes in mice prevented by blockade of adhesion-promoting receptor on macrophages.

Insulin-dependent diabetes mellitus (IDDM) is a disease with an autoimmune aetiology. The non-obese diabetic mouse is a good spontaneous animal model of the human disease, with IDDM developing in 50-80% of female mice by the age of 6 months. The disease can be transferred by splenic T cells from diabetic donors and is prevented by T-cell depletion.

Prevention of insulin-dependent diabetes mellitus in non-obese diabetic mice by transgenes encoding modified I-A beta-chain or normal I-E alpha-chain.

Insulin-dependent diabetes mellitus (IDDM) is a disease with an autoimmune aetiology. The inbred non-obese diabetic (NOD) mouse strain provides a good animal model of the human disease and genetic analysis suggests that, as in man, at least one of the several genes controlling the development of IDDM is linked to the major histocompatibility complex. The NOD mouse does not express I-E owing to a deletion in the promoter region of the I-E alpha-chain gene, and the sequence of NOD I-A beta-chain in the first external domain is unique with His 56 and Ser 57 replacing Pro and Asp, respectively, at these positions.

The involvement of Ly2+ T cells in beta cell destruction.

The non-obese diabetic (NOD) mouse is considered to be a good model of human Type I diabetes mellitus. Both sexes develop insulitis starting at about 6 weeks of age, and onset of diabetes follows at about 30 weeks in females, but later and much less frequently in males. In some mice (but not all) infiltration of the islets leads to selective destruction of insulin-producing beta cells, which is marked by clinically overt diabetes and is thought to be an autoimmune response mediated by T cells.

The pathogenicity of Mycobacterium tuberculosis during chemotherapy.

We used the guinea pig as an experimental model to investigate the pathogenicity of Mycobacterium tuberculosis. Sputum samples were injected subcutaneously into guinea pigs and the animals were killed and an autopsy performed after eight weeks. The likelihood of the sputum samples producing tuberculosis in the guinea pig was related to culture positivity rather than to duration of chemotherapy.

The cellular basis of the local graft-versus-host reaction in rat kidney.

Injection of parental strain rat lymphocytes under the kidney capsule of semi-allogeneic F1 recipients causes a local graft-versus-host reaction (GVHR) characterized by a heavy mononuclear cell infiltrate and renal tubular destruction. Since the cellular events involved may have relevance to allogeneic tissue damage in GVH disease and allograft rejection, a detailed analysis of the rat renal GVH reaction was performed. A purified CD4+ lymphocyte subpopulation was as effective in mediating a local GVHR as unfractionated parental lymphocytes, but neither naive CD8+ nor specifically sensitized CD8+ lymphocytes produced a detectable renal GVHR.

Field trials to determine a suitable injection dose of bovine PPD tuberculin for the diagnosis of bovine tuberculosis in naturally infected cattle.

Biological assays carried out in the Republic of Ireland in naturally sensitized (M. bovis infected) tuberculous cattle have shown that Rotterdam and Weybridge bovine PPD tuberculins issued for routine use in 1981 and 1982 were equipotent with an estimated potency of about 24,000 Community Tuberculin Units (C.T.

The potency of bovine PPD tuberculins in guinea-pigs and in tuberculous cattle.

Potency differences between bovine purified protein derivative tuberculin preparations produced in two different centres and also between preparations produced within these centres, were detected in tuberculous cattle and correlated with potency differences in guinea-pigs. Although assays in groups of guinea-pigs sensitized with either killed Mycobacterium bovis or live BCG identified the weak batches and listed the tuberculins in the same order of potency as the cattle assays, there were nevertheless significant differences between potency estimates according to the mode of sensitization and the preparations compared. The implications for the standardization of tuberculin preparation in general are discussed.