Impact of Disease Heterogeneity on Treatment Efficacy of Immunotherapy in Type 1 Diabetes: Different Shades of Gray

Woittiez, Nicky J C; Roep, Bart O.

doi:10.2217/imt.14.104

Cited by 30 publications

(23 citation statements)

References 58 publications

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“…Furthermore whenever the results of Phase I and Phase II trials were promising, large randomized controlled trials did not reach primary endpoints [52,53]. The main problem resides on the difference between the human and the mouse model, the contribution of a plethora of environmental factors to the pathogenesis, inaccurate dosing, time/duration of treatment and last but not least the heterogeneity of the human disease influenced by different genetic determinants often requiring ‘tailored’ approaches of personalized medicine [54]. …”

Section: Discussionmentioning

confidence: 99%

Use of short interfering RNA delivered by cationic liposomes to enable efficient down-regulation of PTPN22 gene in human T lymphocytes

Perri

Pellegrino

Ceccacci³

et al. 2017

PLoS ONE

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Type 1 diabetes and thyroid disease are T cell-dependent autoimmune endocrinopathies. The standard substitutive administration of the deficient hormones does not halt the autoimmune process; therefore, development of immunotherapies aiming to preserve the residual hormonal cells, is of crucial importance. PTPN22 C1858T mutation encoding for the R620W lymphoid tyrosine phosphatase variant, plays a potential pathophysiological role in autoimmunity. The PTPN22 encoded protein Lyp is a negative regulator of T cell antigen receptor signaling; R620W variant, leading to a gain of function with paradoxical reduced T cell activation, may represent a valid therapeutic target. We aimed to develop novel wild type PTPN22 short interfering RNA duplexes (siRNA) and optimize their delivery into Jurkat T cells and PBMC by using liposomal carriers. Conformational stability, size and polydispersion of siRNA in lipoplexes was measured by CD spectroscopy and DLS. Lipoplexes internalization and toxicity evaluation was assessed by confocal microscopy and flow cytometry analysis. Their effect on Lyp expression was evaluated by means of Western Blot and confocal microscopy. Functional assays through engagement of TCR signaling were established to evaluate biological consequences of down-modulation. Both Jurkat T cells and PBMC were efficiently transfected by stable custom lipoplexes. Jurkat T cell morphology and proliferation was not affected. Lipoplexes incorporation was visualized in CD3+ but also in CD3- peripheral blood immunotypes without signs of toxicity, damage or apoptosis. Efficacy in affecting Lyp protein expression was demonstrated in both transfected Jurkat T cells and PBMC. Moreover, impairment of Lyp inhibitory activity was revealed by increase of IL-2 secretion in culture supernatants of PBMC following anti-CD3/CD28 T cell receptor-driven stimulation. The results of our study open the pathway to future trials for the treatment of autoimmune diseases based on the selective inhibition of variant PTPN22 allele using lipoplexes of siRNA antisense oligomers.

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Section: Discussionmentioning

confidence: 99%

Use of short interfering RNA delivered by cationic liposomes to enable efficient down-regulation of PTPN22 gene in human T lymphocytes

Perri

Pellegrino

Ceccacci³

et al. 2017

PLoS ONE

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“…Accumulating data suggest that type 1 diabetes might be a heterogeneous disease . Insulin/proinsulin may qualify as the primary autoantigen in the HLA DR4‐DQ8‐positive form of T1D, but it can hardly play that role in the HLA DR3‐DQ2‐positive disease form.…”

Section: Is There a Primary Autoantigen In Type 1 Diabetes?mentioning

confidence: 99%

Role of humoral beta-cell autoimmunity in type 1 diabetes

et al. 2016

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Islet cell antibodies (ICA) were found for the first time more than 40 yr ago in patients with autoimmune endocrine deficiencies, including type 1 diabetes (T1D). ICA detected by indirect immunofluorescence represent a heterogeneous group of autoantibodies targeting a series of biochemical autoantigens, such as the protein tyrosine phosphatase related islet antigen 2 (IA-2), the 65 kD isoform of glutamic acid decarboxylase (GA65), and zinc transporter 8 (ZnT8) as well as currently unidentified autoantigens. The general view is that the diabetes-associated autoantibodies are not directly involved in beta-cell destruction but function as biomarkers of an ongoing destructive process. The diabetes-associated autoantibodies remain the strongest predictive marker for future development of T1D. Positivity for multiple (≥2) autoantibodies is highly predictive of clinical disease both among first-degree relatives and in the general population. Autoantibody titers are highly variable during the preclinical phase, but in many cases the titers tend to decrease before diagnosis. The first signs of beta-cell autoimmunity may appear early during the first months of life. The majority of those individuals diagnosed with T1D before puberty seroconvert to autoantibody positivity before the age of 3 yr. The natural course and duration of preclinical diabetes vary substantially from one individual to another. The characteristics of the isotype-specific response during preclinical diabetes appear to be antigen-specific. Diabetes-associated autoantibodies may be useful surrogate markers of the subsequent development of T1D in primary prevention trials. T1D may occur, albeit rarely, in the absence of any signs of humoral autoimmunity at diagnosis.

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“…First, given the huge degree of variation in immunopathology, no single bullet is to be expected as a viable immune intervention therapy for the T1D patient community at large. Instead, disease differentiation and fine diagnosis may move immunotherapy to precision and personalized medicine (10,11). The persistence of both b-cells and insulitis may help explain why abatacept may still work at the supposedly late stage of clinical diagnosis or perhaps explain subgroup (in)efficacies (e.g., apparent lack of efficacy of abatacept in African American patients) (12).…”

mentioning

confidence: 99%

Insulitis Revisited

Roep

2016

Diabetes

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Impact of Disease Heterogeneity on Treatment Efficacy of Immunotherapy in Type 1 Diabetes: Different Shades of Gray

Cited by 30 publications

References 58 publications

Use of short interfering RNA delivered by cationic liposomes to enable efficient down-regulation of PTPN22 gene in human T lymphocytes

Use of short interfering RNA delivered by cationic liposomes to enable efficient down-regulation of PTPN22 gene in human T lymphocytes

Role of humoral beta-cell autoimmunity in type 1 diabetes

Insulitis Revisited

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