Calendário de Defesas e Seminários

Data: Quarta-feira, 11 de Dezembro de 2019 (12:00 - 23:59)



Evaluation of polymorphisms in toll-like receptor genes on the response to thalidomide and prednisone treatment in patients with erythema nodosum leprosum

Orientadora: Dra. Fernanda Sales Luiz Vianna

Avaliador:  Dr. José Artur Bogo Chies 

Erythema nodosum leprosum (ENL) is a severe inflammatory reaction associated with high cytokine levels that occurs in some patients with multibacillary leprosy (MB). Toll-like receptors (TLRs) are elements of the innate immune system that can activate various inflammatory and adaptive immune pathways.  ENL treatment is based on decreasing these cytokines and the most commonly used drugs are prednisone and thalidomide. Prednisone acts by inhibiting the activation of transcription factors, such as nuclear factor nuclear factor NF-kB, whereas thalidomide acts mainly by inhibiting TNF-α expression, decreasing levels of this cytokine. Located on the cell surface, TLR1 receptor recognizes bacterial lipopeptides. In several studies rs4833095 polymorphism in TLR1 gene has been associated with tuberculosis, leprosy and its reactions. TLR2 is capable of forming heterodimers with TLR1 or TLR6, which enables the recognition of a wide variety of microbial components. In some studies, rs3804099 in TLR2 gene was able to influence susceptibility to leprosy and reverse reaction (another reaction of leprosy), in addition to serum levels of some cytokines, such as IL-17, CXCL-10 and IL-6, which were elevated in the presence of the T allele. TLR4 recognizes lipopolysaccharide from gram-negative bacteria. In a study conducted in Brazil, significant differences in cytokine levels IL-17 and IL-1β were observed in leprosy patients with allele A in rs1927914 SNP. TLR6 forms TLR2 heterodimer in a complex including CD14 to recognize diacylated lipoproteins and lipoteichoic acid. Studies have shown that the SNP T allele rs5743810 has a protective effect against the development of tuberculosis. In addition to association with a higher susceptibility to complicated skin infections.  Recently, higher levels of TLR9 and its ligands have been identified in ENL patients. TLR9 gene has several single nucleotide polymorphisms, but two have been described as sufficient to distinguish the four most common TLR9 haplotypes: rs5743836 and rs352140. In this context, the aim of this study is to evaluate the influence of variants in these TLR genes on the response to treatment of ENL with thalidomide and prednisone. So far, 111 ENL patients, selected in different regions of Brazil (RS, CE, MA, and RO) and treated with thalidomide and/or prednisone, were recruited. Clinical data about leprosy, ENL, the treatment, and possible adverse effects were collected. DNA was extracted from saliva samples using the Oragene DNA Extraction Kit (DNA Genotek®) according to the manufacturer's instructions. Generalized Estimating Equation (GEE) method was used to evaluate the influence of TLRs genotypes on the dose variation of thalidomide and prednisone over time. Descriptive frequency analysis was performed on SPSS® version 18 (SPSS,, IIBM, USA). The sample was characterized by a male predominance (77%) and around 40% (n = 41) using multidrug therapy for leprosy during treatment of ENL. The patients were followed for an average of 190 days. The most common adverse effects were neurological (28.5%) and gastrointestinal (19.4%). The average dose of thalidomide used throughout the treatment was 140.7 mg while prednisone 30.6 mg. In this study no influence of TLR2 genetic variations on thalidomide or prednisone doses was observed. However, GEE analysis showed that the different genotypes of TLR1, TLR4 and TLR6 influence thalidomide doses, whereas TLR9 genotypes were able to influence prednisone dose. Thus, it is possible that Toll like receptors may be therapeutic targets for inflammatory conditions,including leprosy and ENL.


Evaluation of Peripheral Neuropathy-Associated Polymorphisms in Thalidomide Treatment in Multiple Myeloma Patients

Orientadora: Dra. Fernanda Sales Luiz Vianna

Coorientadora:  Dra. Clévia Rosset

Avaliadora:  Dra.  Mariana Rodrigues Botton


Multiple Myeloma (MM) is a condition with several signs and symptoms, which frequently appear in patients with average age of 70 years. The diagnosis of MM is characterized by the presence of at least 10% of the clonal plasma cells in the blood or bone marrow and the presence of monoclonal protein in the blood or urine. Treatment of MM is based on autologous hematopoietic stem cell transplantation and chemotherapy regimens. However, one of most important adverse effect of MM treatment is peripheral neuropathy (PN), a condition characterized by degeneration of peripheral nerves. Thalidomide and bortezomib are used in different therapeutical schemes of MM and are the main responsible for PN. Genetic variants of enzymes that act on the metabolism of these drugs or genes that play a fundamental role in the action of these drugs are sources of variation in individual response. The aim of this study is to evaluate the association of genetic variants and the occurrence of PN in MM patients treated with thalidomide and bortezomib. We performed a bibliographic and database search, looking for genes and variants related to PN. We selected four single nucleotide variants that fall in the established criteria in SERPINB2, ABCA1, PKNOX1 and CYP2C19 genes. So far, clinical and demographic characteristics, as well as samples of peripheral blood were collected from 43 MM patients. DNA extracted from these blood samples was genotyped by TaqMan probes and possible associations of the genotypes with PN was investigated. Descriptive analyzes show a mean age of patients is 64 years, 76% of them were submitted to thalidomide treatment regimens, 9.5% were submitted to bortezomib treatment regimens, and 2.4% used thalidomide and bortezomib together. We found that fourteen (45%) of the patients presenting PN. Preliminary results showed that genotypic frequencies of the sample are according to the population frequencies, and so far, these variants are not associated with the occurrence of PN. Data from new patients will continue to be collected and analyzed in order to increase the sample size and clarify the role of these variants in NP. The evaluation of variants regarding the risk or protection for the development of PN can help in the clinic with information for more personalized therapeutic management.

Local  Anfiteatro do Departamento de Genética, Prédio 43312, Campus do Vale/UFRGS
Contato: PPGBM - Av. Bento Gonçalves, 9500 - Prédio 43312 M - Telefone: (51)3308-6722 / E-mail:
por Tamara Moch