Pharmacogenetics: A strategy for personalized medicine for autoimmune diseases

Tavakolpour, Soheil; Darvishi, Mohammad; Ghasemiadl, Mojtaba

doi:10.1111/cge.13186

Cited by 27 publications

(14 citation statements)

References 214 publications

(400 reference statements)

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“…These compounds are very specific, and the results obtained with each mAb have been very positive. However, ~30% of patients with severe diseases remain unresponsive to existing therapies, and the appearance of drug resistance is frequent (48,49). Our present results describe a potentially useful molecular target candidate, BAMBI, and a novel mAb against it, the B101.37 mAb.…”

Section: Discussionmentioning

confidence: 77%

Therapeutic Effects of Anti–Bone Morphogenetic Protein and Activin Membrane‐Bound Inhibitor Treatment in Psoriasis and Arthritis

Álvarez

Augustín

Tamayo

et al. 2020

Arthritis & Rheumatology

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Objective The transforming growth factor β (TGFβ) inhibitor BAMBI (bone morphogenetic protein and activin membrane‐bound inhibitor) has been shown to control differentiation of CD4+ T lymphocytes into either tolerogenic Treg cells or pathogenic Th17 cells, through the regulation of TGFβ and interleukin‐2 (IL‐2) signaling strength. The present study was undertaken to explore the potential beneficial effects of this strategy of pharmacologic inhibition using novel anti‐BAMBI monoclonal antibodies (mAb) in different experimental murine models of chronic skin and joint inflammatory/autoimmune disease. Methods Development of Saccharomyces cerevisiae mannan–induced psoriatic arthritis (MIP) (n = 18–30 mice per group), imiquimod‐induced skin psoriasis (n = 20–30 mice per group), or type II collagen–induced arthritis (CIA) (n = 13–16 mice per group) was analyzed in a total of 2–5 different experiments with either wild‐type (WT) or BAMBI‐deficient B10.RIII mice that were left untreated or treated with mAb B101.37 (mouse IgG1 anti‐BAMBI), a mouse IgG1 anti‐TNP isotype control, anti‐CD25, or anti‐TGFβ mAb. Results Treatment of normal mice with IgG1 anti‐BAMBI mAb clone B101.37 led to expansion of Treg cells in vivo, and had both preventive and therapeutic effects in mice with MIP (each P < 0.05 versus controls). The conferred protection against disease progression was found to be mediated by Treg cells, which controlled the activation and expansion of pathogenic IL‐17–producing cells, and was dependent on the level of TGFβ activity. Furthermore, treatment with B101.37 mAb blocked both the development of skin psoriasis induced by imiquimod and the development of CIA in mice (each P < 0.05 versus controls). Finally, pharmacologic inhibition of BAMBI with the IgM anti‐BAMBI mAb B143.14 also potentiated the suppressive activity of Treg cells in vitro (P < 0.001 versus controls). Conclusion These results in murine models identify BAMBI as a promising new therapeutic target for chronic inflammatory diseases and other pathologic conditions modulated by Treg cells.

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Section: Discussionmentioning

confidence: 77%

Therapeutic Effects of Anti–Bone Morphogenetic Protein and Activin Membrane‐Bound Inhibitor Treatment in Psoriasis and Arthritis

Álvarez

Augustín

Tamayo

et al. 2020

Arthritis & Rheumatology

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“…Interestingly, at the present time IL-17A have become a relevant drug target in various forms of autoimmune and inflammatory diseases, mainly as negative modulators of the secreted protein 13,49 . Two antibodies are currently in Phase IV of drug development for the treatment of immune system diseases, namely, Secukinumab and Ixekizumab (Anatomical Therapeutic Chemical [ATC] code L04AC10 and L04AC13, respectively).…”

Section: Discussionmentioning

confidence: 99%

Genetic polymorphisms of IL17A associated with Chagas disease: results from a meta-analysis in Latin American populations

Strauss

Palma-Vega

Casares-Marfil

et al. 2020

Sci Rep

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Genetic factors and the immunologic response have been suggested to determine the susceptibility against the infection and the outcome of chagas disease. in the present study, we analysed three IL17A genetic variants (rs4711998, rs8193036 and rs2275913) regarding the predisposition to Trypanosoma cruzi infection and the development of chronic Chagas cardiomyopathy (CCC) in different Latin American populations. A total of 2,967 individuals from Colombia, Argentina, Bolivia and Brazil, were included in this study. The individuals were classified as seronegative and seropositive for T. cruzi antigens, and this last group were divided into asymptomatic and ccc. for T. cruzi infection susceptibility, the IL17A rs2275913*A showed a significant association in a fixed-effect meta-analysis after a Bonferroni correction (p = 0.016, OR = 1.21, 95%CI = 1.06-1.41). No evidence of association was detected when comparing ccc vs. asymptomatic patients. However, when ccc were compared with seronegative individuals, it showed a nominal association in the meta-analysis (p = 0.040, oR = 1.20, 95%CI = 1.01-1.45). For the IL17A rs4711998 and rs8193036, no association was observed. in conclusion, our results suggest that IL17A rs2275913 plays an important role in the susceptibility to T. cruzi infection and could also be implicated in the development of chronic cardiomyopathy in the studied Latin American population.Chagas disease caused by the protozoan Trypanosoma cruzi is a parasitic infection endemic in Latin American countries, which is nowadays increasingly becoming a global health problem, due to migration to non-endemic areas 1,2 . Around 6 to 7 million people are estimated to be infected worldwide, mostly in Latin America 1,3 . During the acute phase of the disease, the increase of parasitic load induces an inflammatory process for the control of the pathogen 4 . Ten to thirty years after infection, around 30 to 40% of chronically infected patients can develop cardiomyopathy or/and megaviscera. The symptoms include cardiac conduction abnormalities, myocardial contractile dysfunction, arrhythmias, dysphagia, regurgitation, and severe constipation, among others. The cardiac involvement is the most frequent manifestation of the disease 5,6 . The characteristics of this phase vary in different patients and in different regions of the endemic area 7 .After the infection with T. cruzi, interleukin-17A (IL-17A) is produced by T helper 17 (Th17) cells, subset of CD4+ T cells, and innate lymphoid cells 8,9 . More recently, it has been described that B cells are also an important source of IL-17A and IL-17F, produced as well after T. cruzi infection 10,11 . In response to the infection, IL17-A, induces a rapid proinflammatory cascade of chemokines and cytokines that facilitates the recruitment and activation of neutrophils and monocytes required for the early control of the pathogen by the immune system 12,13 . In the chronic phase of the disease, several studies suggest that the clinical progression of Chagas cardiomyopathy involves th...

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“…Because of the dynamic development of molecular techniques, it has become possible to identify the gene transcripts that could act as new complementary molecular markers for detecting a lack of response to treatment as well as for deciding to change the therapy before adverse phenotypic changes occur [20][21][22]. This is because molecular changes are preceded by phenotypic changes [23] and the molecular marker systems entirely fit the strategy of personalized diagnostics and treatment [24,25].…”

Section: Discussionmentioning

confidence: 99%

mRNA level of ROCK1, RHOA, and LIMK2 as genes associated with apoptosis in evaluation of effectiveness of adalimumab treatment

Krawczyk

Strzałka‐Mrozik

Grabarek³

et al. 2020

Pharmacol. Rep

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Background Psoriasis is a multifactorial autoimmune disease, which underlies the abnormalities of the apoptotic process. In cases of psoriasis and psoriatic arthritis, biological treatment is used. This study aimed to determine any changes in the expression of the genes associated with apoptosis in patients with psoriatic arthritis treated with adalimumab and to assess any phenotypic modifications based on changes in dermatological indexes. Methods The study included 20 patients with psoriatic arthritis treated biologically and 20 healthy volunteers. The research material consisted of peripheral blood mononuclear cells (PBMCs) from which the total RNA was isolated. Changes in the gene expression were determined using oligonucleotide microarrays and RT-qPCR. The clinical condition was assessed based on selected indicators: PASI, BSA [%], DAS28, and DLQI, which were determined every 3 months. Results There were changes in the expression of genes associated with apoptosis. Significant differences were found for ROCK1, RhoA, and LIMK2 expression profiles in PBMCs. At the initial stage of treatment, a decrease in the PASI and BSA rates was observed. At the later stages, the values of these indicators increased once again. There were correlations between the changes in these genes' expression and the dermatological markers. Conclusion Adalimumab influences the expression of genes related to apoptosis and the values of dermatological indicators of patients. Changes in the expression level of genes associated with apoptosis suggest that ROCK1, RhoA, and LIMK2 may be genes that can potentially be indicators of treatment effectiveness and lack of response to biological treatment.

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Pharmacogenetics: A strategy for personalized medicine for autoimmune diseases

Cited by 27 publications

References 214 publications

Therapeutic Effects of Anti–Bone Morphogenetic Protein and Activin Membrane‐Bound Inhibitor Treatment in Psoriasis and Arthritis

Therapeutic Effects of Anti–Bone Morphogenetic Protein and Activin Membrane‐Bound Inhibitor Treatment in Psoriasis and Arthritis

Genetic polymorphisms of IL17A associated with Chagas disease: results from a meta-analysis in Latin American populations

mRNA level of ROCK1, RHOA, and LIMK2 as genes associated with apoptosis in evaluation of effectiveness of adalimumab treatment

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