Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ) is a chronic necrosis of the jawbone that occurs in ≈1-5% of patients receiving bisphosphonate medication for conditions such as osteoporosis and certain cancers. Although the pathogenesis of BRONJ is still uncertain, several recent theories have emerged; these include vascular disruption of the jaw tissue; inappropriate osteoclast activation; and direct cytotoxicity of jaw epithelium. However, despite bisphosphonates having well-documented stimulatory effects on immune cells, and BRONJ being associated with oral microbial infections, an immune-mediated pathology for BRONJ has largely been ignored. Bisphosphonates activate human γδ T cells, specifically those that use T cell receptor (TCR) γ-chain variable-region-9, and TCR δ-chain variable-region-2 (Vγ9Vδ2 T cells). These unconventional T cells typically account for ≈ 1-5% of circulating lymphocytes, make protective responses to microbial challenge, and are promising candidates for cancer immunotherapy. In the context of BRONJ, we have hypothesised that bisphosphonate-mediated activation of jaw-associated Vγ9Vδ2 T cells, in the presence of oral microbiota, may drive the disruption of bone turnover that is central to the disease process. On initiation of these studies, it quickly became apparent that traditional characterisation of Vγ9Vδ2 T cells using CD27/CD45RA was demonstrably sub-optimal, while phenotypic analysis of 63 healthy volunteers revealed an unexpected and surprising degree of Vγ9Vδ2 T cell heterogeneity; both of which are likely to confuse assessment of disease scenarios. Thus, this thesis describes the novel phenotypic and functional characterisation of Vγ9Vδ2 T cells using alternative surface markers and methods of analysis. This reveals that different sets of individuals have different Vγ9Vδ2 T cell “profiles” that predict very different functional capabilities and responses to immunotherapeutic interventions. Using this improved definition of Vγ9Vδ2 T cells, this thesis then describes preliminary investigations of Vγ9Vδ2 T cell development in the human neonatal thymus, and assesses the involvement of Vγ9Vδ22 T cells in a small cohort of eight BRONJ patients.

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Os bisfosfonatos são medicamentos amplamente e efetivamente utilizados para o tratamento de doenças osteolíticas. Entretanto, na cavidade oral, é de particular relevância, pois possuem como efeito adverso a osteonecrose dos maxilares induzida pelo uso de bisfosfonatos. Sua etiopatogenia ainda não é bem estabelecida, os métodos de detecção são insatisfatórios e as terapias recomendadas são por vezes, medidas paliativas e ineficazes. Pouco ainda é sabido sobre o efeito do Ácido Zoledrônico na microestrutura óssea, portanto, propusemo-nos a realizar um estudo em modelo animal que analisasse o trabeculado ósseo da mandíbula através da Micro-CT. Foram utilizados 24 ratos machos (Rattus novergicus, albinus, Wistar), com 12 semanas de vida, divididos em 2 grupos: grupo controle (cloreto de sódio 0,9%) e grupo ácido zoledrônico (ácido zoledrônico 0,6mg/kg). As substâncias foram administradas via intraperitoneal a cada 28 dias em um total de 5 doses. Após 150 dias do início do experimento, foi realizada a eutanásia dos animais e então as amostras foram preparadas e escaneadas (Skyscan 1174) para análise da microestrutura óssea através da Micro- CT. O teste t-student demonstrou diferença estatisticamente significativa (p<0,05) em todos os fatores: volume ósseo, densidade óssea, fator de padrão trabecular, índice de modelo estrutural, espessura trabecular, separação trabecular, porosidade total exceção de número de trabéculas e volume tecidual, demonstrando que há alterações significativas na estrutura trabecular pelo uso de bisfosfonatos. O grupo medicado com ácido zoledrônico comparado ao grupo controle demonstrou trabéculas mais espessas, menos separadas e com menores ligações. / Bisphosphonates are widely and effectively drugs used for the treatment of osteolytic disorders. However, in the oral cavity, this situation is of particular relevance as it can lead to bisphosphonate related osteonecrosis of the jaws. Its etiopathogenesis is still not established, detection methods are unsatisfactory and recommended therapies are sometimes palliative and often ineffective. Little is known about the effect of zoledronic acid on the quality of trabecular bone, therefore, we proposed to conduct a study in an animal model to examine the trabecular bone of the jaw through the Micro-CT. 24 male rats were used (Rattus norvegicus, Albinus, Wistar), with 12 weeks old, divided into 2 groups: control group (sodium chloride 0.9%) and group with zoledronic acid (zoledronic acid 0.6 mg / kg). The substances were administered intraperitoneally every 28 days for a total of 5 doses. After 150 days from the beginning of the experiment, the animals were sacrificed and then the samples were prepared and scanned (Skyscan 1174) for analysis of the bone microstructure through Micro-CT. The \"t-student\" test demonstrated statistically significant differences (p<0.05) in all factors: bone volume, osseous density, trabecular pattern, structure model index, trabecular thickness, trabecular separation, total porosity except trabecular number and tissue volume, demonstrating that there are significant changes in the trabecular structure of the bisphosphonates. Zoledronic Acid compared to control group shows thicker, less separate and lower connected trabeculae.

Os bisfosfonatos são medicamentos amplamente e efetivamente utilizados para o tratamento de doenças osteolíticas. Entretanto, na cavidade oral, é de particular relevância, pois possuem como efeito adverso a osteonecrose dos maxilares induzida pelo uso de bisfosfonatos. Sua etiopatogenia ainda não é bem estabelecida, os métodos de detecção são insatisfatórios e as terapias recomendadas são por vezes, medidas paliativas e ineficazes. Pouco ainda é sabido sobre o efeito do Ácido Zoledrônico na microestrutura óssea, portanto, propusemo-nos a realizar um estudo em modelo animal que analisasse o trabeculado ósseo da mandíbula através da Micro-CT. Foram utilizados 24 ratos machos (Rattus novergicus, albinus, Wistar), com 12 semanas de vida, divididos em 2 grupos: grupo controle (cloreto de sódio 0,9%) e grupo ácido zoledrônico (ácido zoledrônico 0,6mg/kg). As substâncias foram administradas via intraperitoneal a cada 28 dias em um total de 5 doses. Após 150 dias do início do experimento, foi realizada a eutanásia dos animais e então as amostras foram preparadas e escaneadas (Skyscan 1174) para análise da microestrutura óssea através da Micro- CT. O teste t-student demonstrou diferença estatisticamente significativa (p<0,05) em todos os fatores: volume ósseo, densidade óssea, fator de padrão trabecular, índice de modelo estrutural, espessura trabecular, separação trabecular, porosidade total exceção de número de trabéculas e volume tecidual, demonstrando que há alterações significativas na estrutura trabecular pelo uso de bisfosfonatos. O grupo medicado com ácido zoledrônico comparado ao grupo controle demonstrou trabéculas mais espessas, menos separadas e com menores ligações. / Bisphosphonates are widely and effectively drugs used for the treatment of osteolytic disorders. However, in the oral cavity, this situation is of particular relevance as it can lead to bisphosphonate related osteonecrosis of the jaws. Its etiopathogenesis is still not established, detection methods are unsatisfactory and recommended therapies are sometimes palliative and often ineffective. Little is known about the effect of zoledronic acid on the quality of trabecular bone, therefore, we proposed to conduct a study in an animal model to examine the trabecular bone of the jaw through the Micro-CT. 24 male rats were used (Rattus norvegicus, Albinus, Wistar), with 12 weeks old, divided into 2 groups: control group (sodium chloride 0.9%) and group with zoledronic acid (zoledronic acid 0.6 mg / kg). The substances were administered intraperitoneally every 28 days for a total of 5 doses. After 150 days from the beginning of the experiment, the animals were sacrificed and then the samples were prepared and scanned (Skyscan 1174) for analysis of the bone microstructure through Micro-CT. The \"t-student\" test demonstrated statistically significant differences (p<0.05) in all factors: bone volume, osseous density, trabecular pattern, structure model index, trabecular thickness, trabecular separation, total porosity except trabecular number and tissue volume, demonstrating that there are significant changes in the trabecular structure of the bisphosphonates. Zoledronic Acid compared to control group shows thicker, less separate and lower connected trabeculae.