RESUMEN
Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is a rare autosomal recessive long-chain fatty acid oxidation disorder caused by mutations in the ACADVL gene. The myopathic form presents with exercise intolerance, exercise-related rhabdomyolysis, and muscle pain, usually starting during adolescence or adulthood. We report on a 17-year-old boy who has presented with exercise-induced muscle pain and fatigue since childhood. In recent clinical history, episodes of exercise-related severe hyperCKemia and myoglobinuria were reported. Electromyography was normal, and a muscle biopsy showed only "moth-eaten" fibers, and a mild increase in lipid storage in muscle fibers. NGS analysis displayed the already known heterozygote c.1769G>A variant and the unreported heterozygote c.523G>C change in ACADVL both having disease-causing predictions. Plasma acylcarnitine profiles revealed high long-chain acylcarnitine species levels, especially C14:1. Clinical, histopathological, biochemical, and genetic tests supported the diagnosis of VLCAD deficiency. Our report of a novel pathogenic missense variant in ACADVL expands the allelic heterogeneity of the disease. Since dietary treatment is the only therapy available for treating VLCAD deficiency and it is more useful the earlier it is started, prompt diagnosis is essential in order to minimize muscle damage and slow the disease progression.
RESUMEN
Therapy-related myeloid neoplasm (t-MN) is a threatening complication of autologous stem cell transplantation (ASCT). Detecting clonal hematopoiesis (CH) mutations in cryopreserved cells before ASCT has been associated with a higher risk of t-MN, but the evolution of molecular abnormalities from pre-ASCT to t-MN, within the same patient, remains to be elucidated. We evaluated the mutational profile of 19 lymphoma/myeloma patients, at both pre-ASCT and t-MN diagnosis, using a targeted NGS approach; 26 non-developing t-MN control patients were also studied pre-ASCT. At ASCT, we found a higher frequency of CH in patients developing t-MN (58%) than in those who did not (23%) (P = 0.029); mutations in epigenetic (DNMT3A, TET2, and ASXL1) and DNA repair genes (PPM1D, RAD21, TP53, and STAG2) were the most represented. At t-MN, CH increased to 82% of patients. Cumulative mutational burden and variant allele frequency (VAF) also increased at t-MN. CH clones detected at ASCT were found at t-MN in eight out of 16 patients, mainly with stable VAF. Among the new driver mutations appeared at t-MN, TP53 increased from one to 13 mutations, in nine patients; being associated with complex karyotype. Mutations in transcription factor (RUNX1, CEBPA) and intracellular signaling genes (FLT3, RAS genes) also increased from three to 17 mutations in eight patients, presenting with a normal karyotype. Overall, we found that preexisting CH at ASCT rarely causes t-MN directly, but may rather facilitate the appearance of new mutations, especially those involving TP53, RUNX1, and RAS, that can drive the evolution to t-MN of at least two distinct types.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Trastornos Mieloproliferativos , Neoplasias Primarias Secundarias , Hematopoyesis Clonal/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Hematopoyesis/genética , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Mutación , Trastornos Mieloproliferativos/complicaciones , Trastornos Mieloproliferativos/genética , Trastornos Mieloproliferativos/terapia , Neoplasias Primarias Secundarias/genética , Trasplante Autólogo/efectos adversosRESUMEN
We have developed Joubert syndrome (JS)-derived induced pluripotent stem cell (iPSC) lines from dermal fibroblasts biopsied from a female patient harbouring novel compound heterozygous mutations in CC2D2A gene. The newly established iPSC lines provide tremendous promises for development of JS-derived neuronal cell lines to uncover the molecular and cellular mechanisms underlying the pathogenesis of JS and to develop therapeutic interventions for treatment of JS.
Asunto(s)
Anomalías Múltiples , Anomalías del Ojo , Células Madre Pluripotentes Inducidas , Enfermedades Renales Quísticas , Diferenciación Celular , Cerebelo/anomalías , Anomalías del Ojo/genética , Femenino , Fibroblastos , Humanos , Mutación , Retina/anomalíasRESUMEN
We have generated new disease-specific induced pluripotent stem cell (iPSC) lines from skin fibroblasts obtained from a female patient with Joubert syndrome (JS) caused by compound heterozygous mutations in C5orf42 gene. The generated iPSCs offer an unprecedented opportunity to obtain iPSC-derived neurons to investigate the pathogenesis of JS in vitro and to develop therapeutic strategies.
Asunto(s)
Anomalías Múltiples , Anomalías del Ojo , Células Madre Pluripotentes Inducidas , Enfermedades Renales Quísticas , Diferenciación Celular , Cerebelo/anomalías , Anomalías del Ojo/genética , Femenino , Humanos , Mutación , Retina/anomalíasRESUMEN
Activated phosphoinositide 3-kinase delta syndrome 1 (APDS-1) is a recently described inborn error of immunity caused by monoallelic gain-of-function mutations in the PIK3CD gene. We reviewed for the first time medical records and laboratory data of eight Italian APDS-1 patients. Recurrent sinopulmonary infections were the most common clinical feature at onset of disease. Seven patients presented lymphoproliferative disease, at onset or during follow-up, one of which resembled hemophagocytic lymphohistiocytosis (HLH). Genetic analysis of the PIK3CD gene revealed three novel mutations: functional testing confirmed their activating nature. In the remaining patients, the previously reported variants p.E1021K (n = 4) and p.E525A (n = 1) were identified. Six patients were started on immunoglobulin replacement treatment (IgRT). One patient successfully underwent hematopoietic stem cell transplantation (HSCT), with good chimerism and no GVHD at 21 months post-HSCT. APDS-1 is a combined immune deficiency with a wide variety of clinical manifestations and a complex immunological presentation. Besides IgRT, specific therapies targeting the PI3Kδ pathway will most likely become a valid aid for the amelioration of patients' clinical management and their quality of life.
RESUMEN
Ataxia telangiectasia (AT) and Aicardi-Goutières syndrome (AGS) are inherited disorders of immunity with prevalent neurological phenotype. Available treatments are only partially effective, and the prognosis is poor. Induced pluripotent stem cells (iPSCs) are obtained by reprogramming patient somatic cells, preserving the donor individual genetic heritage and creating patient-specific disease models, useful to investigate pathogenesis and drug effects and to develop precision therapies. The aim is to investigate the cytotoxicity of a panel of immunomodulators using iPSCs of patients with AT or different forms of AGS (AGS1, AGS2, and AGS7). iPSCs were obtained by reprogramming AT and AGS patients' cells and, as a control, the BJ normal human fibroblast line, using Sendai virus. Cytotoxic effects of two drugs proposed to treat respectively AT and AGS (dexamethasone and mepacrine) were tested by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay after 72 hours' exposure. Data were obtained also for other immunomodulatory drugs (thioguanine, mercaptopurine, thalidomide, and lenalidomide). Relative expression of genes involved in the tested drug pathways was analyzed. AGS7-derived iPSCs displayed altered viability when treated with a low dose of mepacrine and higher expression of cyclic guanosine monophosphate-adenosine monophosphate synthase, which is the main target for mepacrine action. AGS7-derived iPSCs were also more sensitive to thioguanine, while AGS2 and AT iPSCs were less sensitive to this medication than the BJ-iPSC. All iPSCs were equally sensitive to mercaptopurine and resistant to dexamethasone, thalidomide, and lenalidomide. This work establishes an innovative in vitro model that is useful to investigate the mechanisms of drugs potentially effective in AT and AGS.
Asunto(s)
Ataxia Telangiectasia/tratamiento farmacológico , Enfermedades Autoinmunes del Sistema Nervioso/tratamiento farmacológico , Factores Inmunológicos/farmacología , Células Madre Pluripotentes Inducidas/efectos de los fármacos , Malformaciones del Sistema Nervioso/tratamiento farmacológico , Medicina de Precisión , Ataxia Telangiectasia/genética , Ataxia Telangiectasia/inmunología , Ataxia Telangiectasia/metabolismo , Enfermedades Autoinmunes del Sistema Nervioso/genética , Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Enfermedades Autoinmunes del Sistema Nervioso/metabolismo , Biomarcadores/metabolismo , Línea Celular , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Toma de Decisiones Clínicas , Dexametasona/farmacología , Relación Dosis-Respuesta a Droga , Resistencia a Medicamentos , Predisposición Genética a la Enfermedad , Humanos , Células Madre Pluripotentes Inducidas/inmunología , Células Madre Pluripotentes Inducidas/metabolismo , Lenalidomida/farmacología , Mercaptopurina/farmacología , Malformaciones del Sistema Nervioso/genética , Malformaciones del Sistema Nervioso/inmunología , Malformaciones del Sistema Nervioso/metabolismo , Fenotipo , Valor Predictivo de las Pruebas , Quinacrina/farmacología , Talidomida/farmacología , Tioguanina/farmacologíaRESUMEN
Autosomal recessive osteopetrosis (ARO) is a rare inherited disorder leading to increased bone density with impairment in bone resorption. Among the genes responsible for ARO, the TCIRG1 gene, coding for the a3 subunit of the osteoclast proton pump, is mutated in more than 50% of the cases, increasing the importance of TCIRG1-iPSCs as disease model. We generated 3 iPSC clones derived from Peripheral Blood Mononuclear Cells (PBMCs) of a patient carrying the heterozygous mutations p.Y512X and c.2236 + 1G > A. A Sendai virus-based vector was used and the iPSCs were characterized for genetic identity to parental cells, genomic integrity, pluripotency, and differentiation ability.
Asunto(s)
Células Madre Pluripotentes Inducidas/metabolismo , Osteopetrosis/genética , ATPasas de Translocación de Protón Vacuolares/genética , Humanos , Lactante , Masculino , MutaciónRESUMEN
We report a rare case of a newborn male affected by incontinentia pigmenti, Klinefelter syndrome, and aplasia cutis congenita, who developed severe cutaneous, neurological, and ophthalmological manifestations. Genetic analysis showed the presence of the common mutation of NEMO (exon 4-10 deletion), Klinefelter syndrome karyotype (47 XXY), and random X inactivation. This is in accordance with the severity of involvement of the affected tissues (skin, central nervous system, and retina). Indeed, the patient developed typical skin lesions all over the body, except the head. Equally, multiple lesions diffusely involving both the cortical grey matter and subcortical white matter of the cerebellum and cerebral hemispheres were observed. Discussing current knowledge about the etiopathogenesis of skin and brain lesions in incontinentia pigmenti, our case seems to support the proapoptotic origin of central nervous system involvement. Possibly, incontinentia pigmenti patients suffer an impaired protection against apoptosis at the level of cerebral endothelial cells of small vessels, leading to vascular damage and subsequent ischemic brain lesions.
RESUMEN
We report the generation of three isogenic iPSC clones (UNIBSi007-A, UNIBSi007-B, and UNIBSi007-C) obtained from fibroblasts of a patient with Aicardi Goutières Syndrome (AGS) carrying a homozygous mutation in RNaseH2B. Cells were transduced using a Sendai virus based system, delivering the human OCT4, SOX2, c-MYC and KLF4 transcription factors. The resulting transgene-free iPSC lines retained the disease-causing DNA mutation, showed normal karyotype, expressed pluripotent markers and could differentiate in vitro toward cells of the three embryonic germ layers.
Asunto(s)
Enfermedades Autoinmunes del Sistema Nervioso/genética , Enfermedades Autoinmunes del Sistema Nervioso/patología , Técnicas de Cultivo de Célula/métodos , Línea Celular/patología , Fibroblastos/patología , Células Madre Pluripotentes Inducidas/patología , Mutación/genética , Malformaciones del Sistema Nervioso/genética , Malformaciones del Sistema Nervioso/patología , Ribonucleasa H/genética , Secuencia de Bases , Niño , Femenino , Humanos , Factor 4 Similar a Kruppel , Reproducibilidad de los ResultadosRESUMEN
Aicardi-Goutières syndrome (AGS) is an early-onset monogenic encephalopathy characterized by intracranial calcification, leukodystrophy and cerebrospinal fluid lymphocytosis. To date, seven genes have been related to AGS. Among these, IFIH1 encodes for MDA5, a cytosolic double-stranded RNA receptor, and is responsible for AGS type 7. We generated three isogenic iPSC clones, using a Sendai virus-based vector, starting from fibroblasts of a patient carrying a dominant mutation in IFIH1. All lines were characterized for genomic integrity, genetic uniqueness, pluripotency, and differentiation capability. Our clones might offer a good model to investigate AGS7 pathophysiological mechanism and to discover new biomarkers for this condition treatment.
Asunto(s)
Enfermedades Autoinmunes del Sistema Nervioso/genética , Enfermedades Autoinmunes del Sistema Nervioso/patología , Técnicas de Cultivo de Célula/métodos , Línea Celular/patología , Fibroblastos/patología , Helicasa Inducida por Interferón IFIH1/genética , Mutación/genética , Malformaciones del Sistema Nervioso/genética , Malformaciones del Sistema Nervioso/patología , Adolescente , Secuencia de Bases , Humanos , Células Madre Pluripotentes Inducidas , Masculino , Reproducibilidad de los ResultadosRESUMEN
Fibroblasts from a patient with Aicardi Goutières Syndrome (AGS) carrying a compound heterozygous mutation in TREX1, were reprogrammed into induced pluripotent stem cells (iPSCs) to establish isogenic clonal stem cell lines: UNIBSi006-A, UNIBSi006-B, and UNIBSi006-C. Cells were transduced using the episomal Sendai viral vectors, containing human OCT4, SOX2, c-MYC and KLF4 transcription factors. The transgene-free iPSC lines showed normal karyotype, expressed pluripotent markers and displayed in vitro differentiation potential toward cells of the three embryonic germ layers.
Asunto(s)
Enfermedades Autoinmunes del Sistema Nervioso/genética , Enfermedades Autoinmunes del Sistema Nervioso/patología , Diferenciación Celular , Exodesoxirribonucleasas/genética , Fibroblastos/patología , Células Madre Pluripotentes Inducidas/patología , Mutación , Malformaciones del Sistema Nervioso/genética , Malformaciones del Sistema Nervioso/patología , Fosfoproteínas/genética , Células Cultivadas , Preescolar , Fibroblastos/metabolismo , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Factor 4 Similar a Kruppel , MasculinoRESUMEN
Crohn's disease is a debilitating and incurable chronic inflammatory bowel disease, affecting millions of individuals worldwide, with an increasing frequency. Surgery must be applicable in half of the cases often with a disabling course, and pharmacological treatments may have adverse complications. We generated three isogenic clones of iPSCs from peripheral blood mononuclear cells (PBMCs) of a patient with Crohn's Disease under pharmacological treatment without adverse effects. Sendai virus based vector was used and the iPSCs were characterized for genetic uniqueness, genomic integrity, pluripotency, and differentiation ability. These iPSCs will be a powerful tool to develop tailored therapies.
Asunto(s)
Línea Celular/citología , Células Madre Pluripotentes Inducidas/citología , Diferenciación Celular , Línea Celular/metabolismo , Células Cultivadas , Enfermedad de Crohn/genética , Enfermedad de Crohn/metabolismo , Enfermedad de Crohn/fisiopatología , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/metabolismo , Masculino , Factor 3 de Transcripción de Unión a Octámeros/genética , Factor 3 de Transcripción de Unión a Octámeros/metabolismo , Adulto JovenRESUMEN
The Cri du Chat Syndrome (CdCS) is a genetic disease resulting from variable size deletion occurring on the short arm of chromosome 5. The main clinical features are a high-pitched monochromatic cry, microcephaly, severe psychomotor and mental retardation with characteristics of autism spectrum disorders such as hand flapping, obsessive attachments to objects, twirling objects, repetitive movements, and rocking. We reprogrammed to pluripotency peripheral blood mononuclear cells derived from a patient carrying large deletion on the short arm of chromosome 5, using a commercially available non-integrating expression system. The iPSCs expressed pluripotency markers and differentiated in the three embryonic germ layers.
Asunto(s)
Técnicas de Reprogramación Celular , Síndrome del Maullido del Gato , Células Madre Pluripotentes Inducidas , Leucocitos Mononucleares , Adulto , Síndrome del Maullido del Gato/genética , Síndrome del Maullido del Gato/metabolismo , Síndrome del Maullido del Gato/patología , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Células Madre Pluripotentes Inducidas/patología , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/patología , MasculinoRESUMEN
BACKGROUND: Early onset dementias (EOD) are rare neurodegenerative dementias that present before 65 years. Genetic factors have a substantially higher pathogenetic contribution in EOD patients than in late onset dementia. OBJECTIVE: To identify known and/or novel rare variants in major candidate genes associated to EOD by high-throughput sequencing. Common-risk variants of apolipoprotein E (APOE) and prion protein (PRNP) genes were also assessed. METHODS: We studied 22 EOD patients recruited in Memory Clinics, in the context of studies investigating genetic forms of dementia. Two methodological approaches were applied for the target-Next Generation Sequencing (NGS) analysis of these patients. In addition, we performed progranulin plasma dosage, C9Orf72 hexanucleotide repeat expansion analysis, and APOE genotyping. RESULTS: We detected three rare known pathogenic mutations in the GRN and PSEN2 genes and eleven unknown-impact mutations in the GRN, VCP, MAPT, FUS, TREM2, and NOTCH3 genes. Six patients were carriers of only common risk variants (APOE and PRNP), and one did not show any risk mutation/variant. Overall, 69% (nâ=â9) of our early onset Alzheimer's disease (EAOD) patients, compared with 34% (nâ=â13) of sporadic late onset Alzheimer's disease (LOAD) patients and 27% (nâ=â73) of non-affected controls (ADNI, whole genome data), were carriers of at least two rare/common risk variants in the analyzed candidate genes panel, excluding the full penetrant mutations. CONCLUSION: This study suggests that EOD patients without full penetrant mutations are characterized by higher probability to carry polygenic risk alleles that patients with LOAD forms. This finding is in line with recently reported evidence, thus suggesting that the genetic risk factors identified in LOAD might modulate the risk also in EOAD.
Asunto(s)
Demencia/genética , Secuenciación de Nucleótidos de Alto Rendimiento/tendencias , Edad de Inicio , Anciano , Alelos , Apolipoproteínas E/genética , Proteína C9orf72/genética , Femenino , Estudios de Asociación Genética , Variación Genética , Humanos , Masculino , Persona de Mediana Edad , Presenilina-2/genética , Proteínas Priónicas/genética , Estudios Retrospectivos , Medición de RiesgoAsunto(s)
Linfocitos B/inmunología , Linfocitos T CD4-Positivos/inmunología , Ligando de CD40/inmunología , Senescencia Celular/inmunología , Células Asesinas Naturales/inmunología , Adulto , Linfocitos B/metabolismo , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/metabolismo , Ligando de CD40/deficiencia , Humanos , Células Asesinas Naturales/metabolismo , Activación de Linfocitos/inmunología , Recuento de Linfocitos , MasculinoRESUMEN
Understanding the biological and molecular processes underlying human pathologies is fundamental in order to develop innovative approaches to treat or prevent them. Among the technologies that could provide innovative disease models, induced pluripotent stem cells (iPSCs) is one of the most promising. Indeed, one application of this technology is patient-specific disease modeling. iPSCs obtained by reprogramming patients' cells collected from accessible tissues, have the unique capability to differentiate, under an adequate stimulus, into any human cell type. In particular, iPSCs technology can be applied to study drug adverse effects, that is a key part of the drug discovery process. Indeed, drug induced adverse effects are among the most common causes that lead to abandon the development of new candidate therapeutic molecules, increasing the cost of drug discovery. An innovative strategy that could be used in drug design to solve drug attrition rate, and to establish innovative pharmacological models, could be the application of iPSCs technology in the early stage of the drug discovery process to model druginduced adverse events. In this review, recently developed disease models based on iPSCs will be discussed, with a particular focus on available models of drugs' adverse effect, in particular hepatic/pancreatic toxicity.
Asunto(s)
Células Madre Pluripotentes Inducidas/metabolismo , Modelos Biológicos , Reprogramación Celular , Niño , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiología , Enfermedad Granulomatosa Crónica/tratamiento farmacológico , Enfermedad Granulomatosa Crónica/patología , Humanos , Células Madre Pluripotentes Inducidas/citología , Hígado/efectos de los fármacos , Hígado/metabolismo , Páncreas/efectos de los fármacos , Páncreas/metabolismo , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/toxicidadAsunto(s)
Síndrome de Inmunodeficiencia con Hiper-IgM/enzimología , Síndrome de Inmunodeficiencia con Hiper-IgM/inmunología , Células Asesinas Naturales/enzimología , Células Asesinas Naturales/inmunología , Fosfatidilinositol 3-Quinasas/metabolismo , Estudios de Casos y Controles , Degranulación de la Célula , Fosfatidilinositol 3-Quinasa Clase Ia , Citotoxicidad Inmunológica , Humanos , Síndrome de Inmunodeficiencia con Hiper-IgM/genética , Interferón gamma/biosíntesis , Células K562 , Mutación , Fosfatidilinositol 3-Quinasas/genética , Transducción de SeñalRESUMEN
Chronic progressive external ophthalmoplegia is a mitochondrial disorder usually caused by single or multiple mitochondrial DNA (mtDNA) deletions and, more rarely, by maternally inherited mtDNA point mutations, most frequently in tRNA genes (MTT). We report on a patient presenting with a progressive eyelid ptosis with bilateral ophthalmoparesis, dysphagia, dysphonia and mild proximal limb weakness associate with a mild movement disorder characterized by abnormal involuntary movements involving head and limbs, imbalance and gait instability. Muscle biopsy demonstrated the presence of ragged red fibers and several cytochrome-C-oxidase negative fibers. Molecular analysis showed the novel m.5613T > C heteroplasmic mutation in the mitochondrial tRNA(Ala) gene (MTTA) which disrupts a conserved site and fulfills the accepted criteria of pathogenicity. Moreover, a 38 CAG trinucleotide repeat expansion was found on the huntingtin gene, thus configuring a singular CPEO/"reduced penetrance" Huntington disease "double trouble". With this novel MTTA point mutation, we extend the spectrum of provisional pathogenic changes in this gene, which is a very rare site of pathogenic mutation, and confirm that clinical expression of these mutations is hardly ever heterogeneous, including myopathy and CPEO. Mitochondrial involvement is an emerging key determinant in the pathogenesis of Huntington disease and it is well known that mutant huntingtin influences the mitochondrial respiratory complexes II and III. A synergist effect of the HTT and MTTA mutations on respiratory chain function may be hypothesized in our patient and should be regarded as a spur for further studies on the mtDNA/HTT reciprocal interactions.
RESUMEN
Induced pluripotent stem cells (iPSC) can be produced from adult cells by transfecting them with a definite set of pluripotency-associated genes. Under adequate growth conditions and stimulation iPSC can differentiate to almost every somatic lineage in the body. Patients' derived iPSC are an innovative model to study mechanisms of adverse drug reactions in individual patients and in cell types that cannot be easily obtained from human subjects. Proof-of concept studies with known toxicants have been performed for liver, cardiovascular and central nervous system cells: neurons obtained from iPSC have been used to elucidate the mechanism of chemotherapy-induced peripheral neuropathy by evaluating the effects of neurotoxic drugs such as vincristine. However, no study has been performed yet on pancreatic tissue and drug induced pancreatitis. Thiopurines (azathioprine and mercaptopurine) are immunosuppressive antimetabolite drugs, commonly used to treat Crohn's disease. About 5% of Crohn's disease patients treated with thiopurines develop pancreatitis, a severe idiosyncratic adverse event; these patients have to stop thiopurine administration and may require medical treatment, with significant personal and social costs. Molecular mechanism of thiopurine induced pancreatitis (TIP) is currently unknown and no fully validated biomarker is available to assist clinicians in preventing this adverse event. Hence, in this review we have reflected upon the probable research applications of exocrine pancreatic cells generated from patient specific iPS cells. Such pancreatic cells can provide excellent insights into the molecular mechanism of TIP. In particular three hypotheses on the mechanism of TIP could be explored: drug biotransformation, innate immunity and adaptative immunity.