published_or_final_version / Obstetrics and Gynaecology / Doctoral / Doctor of Philosophy

Certain strains of mice, e.g. C57BL/6, are highly resistant to serious infections with the protozoan pathogen, Leishmania major, whereas other strains, e.g. BALB/c, are not. It has beenproposed that interferon gamma (IFN-y) is one of the most critical lymphokines produced in a protective response to these intracellular pathogens. IFN-y has been classified as a Thi lymphokine produced by the Thl subset of T lymphocytes which not only activates macrophages to kill the protozoa but also helps regulates the immune system overall to form a lasting immunity to the microorganism (4,19). Mice susceptible to L. major arethought to produce inadequate amounts of IFN-y and instead produce an excessive amount of a Th2 lymphokine, IL-4, produced by Th2 T cells. (6) We have previously found that prophylactic treatment with cyclosporine A (CsA), a T cell specific immunosuppressant, reduces the susceptibility of the BALB/c to L. major by either preventing disease entirely or delaying itsdevelopment significantly (19). In this murine model, it may be that CsA causes a switch from the production of the less protective Th2 lymphokines to the more protective Thl lymphokines. In order to test this hypothesis we examined the IFN-y produced by lymph node and spleen cells over time after infection in three groups of mice: C57BL/6, BALB/c and cyclosporine- protected BALB/c. Interestingly, cells taken from all three groups of mice were able to secrete IFN-y in vitro in response to co-culture with Leishmania, antigens. The pattern of secretion over time, however, varied and may indicate a significant difference in the animals' response to the pathogen. In addition to this work, we also examined the ability of another immunosuppressant, FK506, which is very similar in action to but much less toxic than CsA, to induce enhanced resistence to L. major. FK506 also appears to be effective in reversing the susceptibility of the BALB/c mice towards this pathogen with much less apparent toxicity. / Department of Biology

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Myeloid-derived suppressor cells (MDSC), emerging during tumor growth or chronic inflammation play a critical role in regulating T cell function. However, mechanisms governing the generation of these cells remain unclear, and need to be further defined. Using a DSS-induced colitis and recovery model, we characterized the dynamic changes within myeloid compartments and the emergence of MDSC during active and resolution phases of inflammation. We show that the immature myeloid compartment expands in bone marrow (BM) specifically at the resolution phase of inflammation during colitis transition to recovery. Additionally, we found enhanced levels of IL-17 in the serum of colitis mice tightly correlates with expansion of the IMC compartment, and is likely the factor responsible for expansion of these cells. Our study also determined that the expanded population of myeloid cells underwent a functional reprogramming event. In particular, two major functional changes occurred when colitic mice were allowed to recover: 1) CD11b+Gr-1+ myeloid cells in bone marrow and spleen acquired T cell suppressive functions, and 2) acquired the ability to enter into circulation from BM, confirming previously reported characteristics of MDSC. Additionally, we determined that acquired migratory capability in the low density myeloid cells isolated from resolution time points was due to enhanced surface expression of chemokine receptor CXCR2. Furthermore, we determined that after mobilization of MDSC from the bone marrow, these cells collected in the T cell-rich spleens, where they effectively functioned to suppress T cell proliferation. Through these acquired functions, our study determines a protective role for MDSC during the recovery phase of post-acute inflammation during persistent DSS-induced colitis.

Resumo: A resposta imune na leishmaniose pode resultar em uma polarização da subpopulação dos linfócitos T, levando a um fenótipo celular distinto, que resultam em proteção imune ou exacerbação da doença. As leishmânias persistem no organismo tanto em infecções assintomáticas como após o tratamento, representando risco em condições de imunossupressão. O objetivo deste trabalho foi avaliar o efeito da infecção e da imunossupressão com dexametasona associada à pentoxifilina, sobre o peso dos animais, peso do baço, carga parasitária do baço e do fígado, e da imunopatologia quanto à produção de IFN-γ, IL-10, IL-4 e IL-2 em cultura de células esplênicas de camundongos Balb/c infectados com Leishmania chagasi. A infecção não alterou o ganho de peso dos animais, mas sim o peso e o tamanho do baço. A imunossupressão utilizando a dexametasona associada à pentoxifilina afetou tanto ganho de peso, quanto o peso e o tamanho do baço, de animais infectados e não infectados. A imunossupressão não alterou significativamente o curso da carga parasitária, tanto do baço, como do fígado. A dexametasona e a pentoxifilina afetaram a produção das citocinas estudadas, mas não direcionaram o perfil de resposta Th1/Th2 nos animais infectados. / Abstract: The immune response in leishmaniasis can result in a polarization of a subpopulation of T lymphocytes, leading to a different cell phenotype, resulting in immune protection or exacerbation of the disease. Leishmanias persist in the body both in asymptomatic infections and after the treatment, representing risk in terms of immunosuppression. The objective of this study was to evaluate the effect of infection and immunosuppression with dexamethasone associated with pentoxifylline on the weight of the animals, weight of the spleen, the parasitic load in the spleen and liver, and immunopathology on the production of IFN-γ, IL - 10, IL-4, and IL-2 in spleen cell culture of Balb/c mice infected with Leishmania chagasi. The infection did not alter the animals' weight gain, but the weight and size of the spleen increased. The immunosuppression using dexamethasone associated with pentoxifylline affected both weight gains, as the weight and size of the spleen of infected and not infected animals. The immunosuppression did not alter significantly the course of the parasite burden of the spleen and the liver. Dexamethasone and pentoxifylline affected the studied cytokines production, but not influenced the profile of Th1/Th2 response in infected animals. / Orientador: Helio Langoni / Coorientador: Luciane Alarcão Dias-Melício / Banca: Angela Maria Victoriano de Campos / Banca: Lisiane de Almeida Martins / Mestre

It is well established that females are more immunocompetent than males as evidenced by higher humoral antibody titers, lowered susceptibility to infection, and more efficient graft rejection. Furthermore, females also exhibit a much higher incidence of autoimmune disease. These observations have led investigators to believe that the male hormonal environment may play a key role in the regulation of immune response. For this reason, this study is concerned with the expression of autoimmunity and of immune function in the mouse. This study included the New Zealand Black (NZB) mouse strain, as an animal model for human SLE, as well as normal DBA/2 and Balb/c strains. Animals were administered testosterone via subcutaneous implants in silastic tubing or by injection. Mice used were intact females, intact males and castrated males. Animals were otherwise untreated or had been exposed to a sublethal dose (400-550 rads) of irradiation. Target organ weight changes, immune capacity and peripheral blood picture changes were measured.

Typescript (photocopy) / 199 leaves : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (M.D.)--Dept. of Medicine, University of Adelaide, 1981

Bibliography: leaves 234-314. Examines the role of vascular endothelial cells in inflammation with particular reference to their participation in the immune response directed against a vascularised allograft (kidney)

Typescript (photocopy)

"February 1977." Includes bibliographical references (leaves [105]-[120]) The malignant transformation, and the relevance of developmental antigens to the cancer process, is broadly reviewed. The two developmental antigens - foetal and placental - are then examined in experimental mouse and rat tumour systems.