Diabetes. Breast may well be best.
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Animals↗
Biomedical subjects
A Cooke
Publications and source records attributed to A Cooke.
A thyroxine-containing peptide can induce murine experimental autoimmune thyroiditis.
A synthetic peptide based on a sequence containing thyroxine at position 2553 in thyroglobulin (Tg), and already shown to be recognized by two clonotypically distinct murine Tg autoreactive T cell hybridomas, can trigger primed lymph node cells to transfer thyroiditis to naive recipients. Donor lymph node cells could be prepared from mice immunized either with intact mouse Tg or with this peptide itself. After a second exposure to the priming antigen in vitro, both these populations induced 100% thyroiditis in recipient animals. The importance of the T4 residue in the development of disease was demonstrated by the failure of Tg tryptic peptides depleted of T4 to stimulate pathogenic effectors in vitro, even when the lymph node cells had been taken from mice primed with whole Tg. We conclude that this T4-containing 12mer sequence is a major thyroiditogenic epitope in CBA/J mice although we cannot exclude the possibility that there are other pathogenic epitopes present in the whole Tg molecule.
Animals↗
Altered course of visceral leishmaniasis in mice expressing transgenic I-E molecules.
Previous studies had shown that the outcome of infection with Leishmania donovani was exquisitely sensitive to the influence of the major histocompatibility complex. In this study, we have examined the course of infection in non-obese diabetic (NOD) and NOD-E-3 mice, the latter expressing an I-E molecule as a result of transgenic introduction of the wild-type Ed alpha gene. Introduction of this transgene significantly altered the course of infection allowing for enhanced parasite multiplication in the viscera from day 14 to day 28. This was associated with both a delayed and reduced tissue granulomatous response in NOD-E-3 mice. In vitro, spleen cells from these mice produced equivalent levels of interferon (IFN)-gamma during the early phase of infection but this originated from populations having a different balance of T cells subsets. In NOD mice CD8+ T cells contribute substantially to the total levels of IFN-gamma produced, but in transgenic mice the contribution from this subset is significantly decreased. This is reflected in a reduction in the proportion of Leishmania-specific CD8+ T cells, which could only partially be accounted for by deletion of V beta 5- and V beta 3-expressing CD8+ T cells in NOD-E-3 mice. This study highlights the impact of the introduction of a class II gene product on disease outcome and unexpectedly on the functional potential of CD8+ T cells.
Animals↗
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. This tolerance can be achieved even when diabetogenic cells are already in the pancreas. Primary responses to antigens given after therapy has ceased are normal and secondary responses to antigens seen prior to, but not during, the period of antibody therapy can remain unaffected. This suggests that intervention with selected CD4 antibodies may have significant advantages over and above that provided not only by conventional immunosuppression but also over that provided by a depleting antibody.
Animals↗
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. Furthermore, anti-H-2 Kb cytotoxic responses could not be generated using responder T cells from transgenic mice but T cells from the same mice proliferated, in the presence of interleukin-2, in response to stimulator cells expressing H-2 Kb. Tolerance to H-2 Kb is induced in the thymus since CBA mice grafted with thymus tissue from transgenic mice fail to reject H-2 Kb disparate skin grafts. However, experiments with double-transgenic mice also expressing a T cell receptor with anti-H-2 Kb specificity reveal that tolerance induction is not brought about by elimination of thymocytes bearing H-2 Kb-reactive receptors. Instead, a non-deletional mechanism which results in down-modulation of both CD8 and T cell receptor expression in peripheral T cells correlates with the induction of tolerance in these mice. These data reveal that extremely low levels of self-antigen expression in the thymus are sufficient to induce tolerance via non-deletional mechanisms.
Animals↗
The forces driving autoimmune disease.
There are two classes of autoimmune disease, organ-specific and non-organ specific or systemic. That cells producing autoantibodies are selected by antigen is strongly suggested by the presence of mutations and high affinity antibody. T-cells are pivotal in all forms of autoimmunity as evidenced by the therapeutic benefit of anti-T-cell monoclonals such as anti-CD4, and the frequent development of high affinity IgG autoantibodies. The production of anergic T-cells by the use of non-depleting anti-CD4 in the presence of antigen is discussed with particular reference to its potential for immunological intervention in autoimmune disease. It is possible to identify T-cell epitopes in organ-specific autoimmunity using pathogenic T-cell clones or hybridomas to identify the peptide sequences which are reactive. Antigen-specific therapy may ultimately be based on such peptide epitopes. The specificity of the T-cells in systemic autoimmunity is still obscure, but there is some evidence that reactivity with certain germ-line idiotypes can lead to the development of systemic autoimmunity. The possibility of stimulating B-cells specific for auto-antigens such as DNA becomes feasible if a complex of antibody and DNA is taken up by these specific B-cells and processed idiotype is presented to T-helpers specific for those idiotype epitopes. Evidence is presented that there may be pre-existing defects in the target organ in certain organ-specific disorders, and the evidence for a glycosylation defect in the IgG in patients with rheumatoid arthritis is explored. It is noted that the spouses of probands with rheumatoid arthritis is explored. It is noted that the spouses of probands with rheumatoid arthritis also tend to have this glycosylation defect and this raises the possibility of an effect due to an environmental factor, such as a microbial infection. Molecular mimicry of autoantigens by microbes can stimulate autoreactive cells by their cross-reactivity. It is emphasized that cross-reaction which gives rise to the priming of autoreactive T-cells could give rise to the establishment of a chronic autoimmune state. In animals with normal regulatory immune systems, such induced autoimmunity is ultimately corrected and it is only in animals where there are defects in regulation, that autoimmunity persists. Thus, there are many factors giving rise to autoimmunity, and the diseases are rightly regarded as multifactorial in origin.
Amino Acid Sequence↗
Thyroid autoimmunity.
Antigenic structure remains a major focus in thyroid immunology. The genes for three major thyroid antigens--thyroglobulin, thyroid peroxidase and the thyrotropin receptor--were sequenced in the late 1980's, and epitopes for antibody and T cells have been reported within the last year. In addition, new evidence for selective use of T-cell receptor V gene segments in human thyroid infiltrates may point the way to specific immunotherapy.
Autoantigens↗
Induction of adjuvant arthritis in mice.
Adjuvant arthritis, induced by injections of Freund's complete adjuvant into the footpads of some rat strains, has been recognized as a useful animal model for many years. There has, however, been notable lack of success in reproducing this model in other species. We now describe the development of adjuvant arthritis in healthy strain mice approximately 2 months after injection of Freund's complete adjuvant. Although the clinical appearance of the mice and the joint histopathology closely resemble the adjuvant arthritis reported in the rat, we were unable to detect rheumatoid factor in sera from the affected animals. In parallel studies of T cell proliferation, affected animals responded to some mycobacterial antigens but not to the 65-kD heat shock protein of Mycobacterium tuberculosis, suggesting that some other epitope is important in the development of the disease.
Animals↗
The implications of the failure to generate autoantibody-producing hybridomas from rat erythrocyte-immunized mice.
Injection of mice with rat erythrocytes (RRBC) has long been thought to provide an experimental model in which suppressor T cells (Ts) control autoimmunity. The basis of this is that whilst mice immunized with RRBC produce an antibody response, of which a proportion cross-reacts with autologous red cells, the RRBC-immunized recipients of RRBC-primed spleen cells make no, or little, autoantibody, and secondly because the transfer of this autoantibody-specific suppression can be abrogated by T-cell depletion of transferred spleen cells. Here an alternative explanation of these phenomena is described.
Animals↗
Adjuvant composition determines the induction of type II collagen-induced arthritis.
In this study we have investigated the influence of adjuvant composition on the development of collagen-induced arthritis and of anti-collagen type II specific B- and T-cell responses following immunization with type II collagen. DBA/l mice immunized with bovine collagen type II emulsified in complete Freund's adjuvant (CFA) containing Mycobacterium tuberculosis strain H37Ra developed footpad swelling indicative of arthritis. Animals immunized with collagen type II plus CFA containing Mycobacterium butyricum, or incomplete Freund's adjuvant showed no significant increase in footpad width. Induction of anti-CII specific T-cell proliferation was also dependent upon immunization with CII plus CFA containing M. tb H37RA. In contrast, ovalbumin-reactive T-cell proliferation was unaffected by the species of mycobacteria, indicating that the difference in adjuvant activity of the mycobacterial species is specific for anti-collagen type II T-cell responses. Antibody response to collagen type II, unlike T-cell responses, was not significantly different using the two adjuvants. This study therefore demonstrates that murine collagen-induced arthritis requires immunization with collagen type II together with complete Freund's adjuvant containing Mycobacterium tuberculosis H37RA. Since only this combination of antigen and adjuvant induces detectable arthritis and T-cell responses against collagen type II, while antibody synthesis does not have such stringent adjuvant requirements, this suggests that the development of the full pattern of the collagen-induced arthritis disease requires synergistic activation of both humoral and cell-mediated responses.
Adjuvants, Immunologic↗
The influence of adjuvants on the generation of autoantibody and specific suppression in rat erythrocyte-immunized mice.
A number of adjuvants were investigated for their ability to modulate either the autoimmune response induced in mice by immunization with rat erythrocytes (RRBC) or the ability of RRBC-primed spleen cells to suppress the induction of anti-red cell autoimmunity in recipient mice. The inability of the agents used to do so is discussed on the background of models used to explain the generation of suppression in this system.
Adjuvants, Immunologic↗
The influence of I-E on the generation of autoantibody and specific suppression in rat erythrocyte-immunized mice.
A proportion of the antibodies produced by mice in response to the injection of rat erythrocytes (RRBC) cross-react with autologous red cells. When spleen cells from mice so immunized are transferred to naive syngeneic recipients, the recipient mice produce high anti-RRBC antibody titres but little or no autoantibody. This phenomenon has been attributed to the action of suppressor T cells. To date, the only mouse strain which consistently fails to demonstrate specific suppression of the autoantibody response is the SJL, which lacks the I-E molecules suggested to be important in the generation of suppressor T cells. The results presented here show that some, but not all, I-E negative strains of mice are capable of exhibiting transferable suppression of RRBC-induced antibodies.
Animals↗
Glutathione S-transferase 2 shows an RFLP with BstEII/TaqI double digest.
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Chromosomes, Human, Pair 6↗
Identification of a thyroxine-containing self-epitope of thyroglobulin which triggers thyroid autoreactive T cells.
Although thyroglobulin (Tg), the thyroid prohormone, is well known as a T cell dependent autoantigen in human and experimental autoimmune thyroid disease, very little is known about the molecular basis of Tg recognition by T cells. In this paper, we have characterized the epitopes recognized by two clonotypically distinct, murine Tg autoreactive T cell hybridomas, CH9 and ADA2. In vitro iodination of a Tg preparation which was deficient in in vivo organified iodine was first used to confirm our previous observation that these T cells recognize iodination-related epitopes in the Tg molecule. Affinity chromatography of tryptic peptides derived from normally iodinated human Tg revealed that these epitopes were exclusively located in thyroxine (T4) containing peptides. Through the use of synthetic T4-containing peptides, representing the four major hormonogenic sites in Tg, we demonstrated that both CH9 and ADA2 recognize an epitope containing the T4 at position 2553 in human Tg. Sets of overlapping 5mer to 12mer peptides around this T4 showed that the most potent peptide was a 9mer beginning at Asp 2551. The T4 was shown to be a critical residue, since its replacement with any of the 20 naturally occurring amino acids produced only nonstimulatory peptides. Since the T cell hybridomas could also be stimulated by major histocompatibility complex class II positive (interferon-gamma-treated) thyroid epithelial cells in vitro, and their parent T cell lines can induce thyroiditis on adoptive transfer, the T4-containing Tg sequence described here is implicated as a pathogenic epitope in murine thyroid autoimmunity.
Amino Acid Sequence↗
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. The infiltrate is heterogeneous with respect to V beta usage. Inflammatory macrophages (Mac-1+, F4/80+) can be detected at peri-islet locations at 1 week after transfer and continue to be recruited during the disease process. Their presence at the initiation of disease suggests that their primary function may be autoantigen presentation. Increased expression of major histocompatibility complex (MHC) class I molecules is observed on both endocrine and exocrine tissue in areas of intra-islet infiltration. MHC class II and ICAM-1 expression was restricted to the cells constituting the inflammatory infiltrate. Expression of these molecules was not observed on beta cells implying that presentation of autoantigen by the beta cell itself does not play a role in the beta cell destruction in NOD mice.
Animals↗
Estimating the risk of a fetal autosomal trisomy at mid-trimester using maternal serum alpha-fetoprotein and age: a retrospective study of 142 pregnancies.
Risks appropriate for mid-trimester prenatal screening for autosomal trisomies have been estimated from a combination of maternal age and maternal serum (MS) alpha-fetoprotein (AFP) levels at 16-20 weeks gestation. Published data on the frequency of Down's syndrome births relative to maternal age were modified to include the additional age-related frequency of trisomy 18 and trisomy 13 cases to provide an overall risk for an autosomal trisomy at mid-trimester. MSAFP results from a retrospective study of 142 affected (114 trisomy 21, 19 trisomy 18, and 9 trisomy 13) and 113,000 unaffected pregnancies were converted to multiples of the appropriate gestational median (MOM). The AFP levels in the autosomal trisomy pregnancies were found to be significantly reduced at 0.72 MOM of the unaffected pregnancies. Risks (likelihood ratios) were derived from the overlapping log Gaussian distributions for affected and unaffected pregnancies and combined with maternal age risks to give the overall odds of an affected pregnancy. A mid-trimester cut-off risk of 1:280 gave an estimated 37 per cent detection rate for autosomal trisomies in the west of Scotland population for a follow-up (false-positive) rate of 6.6 per cent. These figures compare with a 30 per cent detection and 6.7 per cent false-positive rate if age 35 years and over is used as the sole criterion for selection of at-risk pregnancies.
Adolescent↗
The development of insulin-dependent diabetes mellitus in non-obese diabetic mice: the role of CD4+ and CD8+ T cells.
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Animals↗
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. These results demonstrate that Qa-2 molecules can behave as major transplantation antigens, as do closely related H-2 molecules. Failure of Qa-2 molecules to provoke strong T-cell responses in non-transgenic mice is probably due to the very low level of expression of Qa-2 molecules in skin keratinocytes from such mice since these cells express increased levels of Qa-2 molecules in all Qa-2 transgenic mice.
Animals↗