The Experts below are selected from a list of 1302 Experts worldwide ranked by ideXlab platform
Rosa Bacchetta - One of the best experts on this subject based on the ideXlab platform.
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Immunoregulatory cell therapy with lentiviral-mediated FOXP3 converted CD4+ T cells into Treg cells: towards the proof-of-concept application in IPEX Syndrome
Cytotherapy, 2019Co-Authors: Yohei Sato, Maria Grazia Roncarolo, Laura Passerini, Rosa BacchettaAbstract:Background & Aim FOXP3 is an essential transcription factor for the regulatory T cell (Treg) function and therefore is a key regulator for the tolerance maintenance. Treg cell therapy, either with freshly isolated or expanded in vitro, has been proven to be safe but still challenging because of difficulties in isolating sufficient number of pure Treg cells, stability of the expanded preparations and Treg plasticity in vivo under pro-inflammatory conditions. The key role of FOXP3 and Treg cells in immune function is exemplified by immune dysregulation, polyendocrinopathy, enteropathy, X-linked Syndrome (IPEX), a monogenic primary immune regulatory disease caused by mutations in FOXP3, that lead to impaired Treg cell function and early onset autoimmune manifestations. Our recent international retrospective study demonstrated suboptimal disease-free survival from current therapeutic options such as immunosuppression and allogeneic hematopoietic stem cell transplantation. Therefore, there is a great unmet medical need in patients with IPEX Syndrome. Methods, Results & Conclusion We investigated lentiviral FOXP3 gene transfer (LV-FOXP3) in CD4+ T cells as an innovative approach to generate in large number stable Treg cells that could provide therapeutic benefit to IPEX patients lacking functional Treg. We have shown that LV-FOXP3 can converts IPEX patients-derived CD4+ effector T cells into Treg-like cells (CD4LV-FOXP3 T cells). To better investigate the safety and efficacy of this approach and to make it suitable for large scale GMP generation of CD4LV-FOXP3 T cells, we optimized the original lentiviral vector and we assessed the phenotype and function of CD4LV-FOXP3 T cells both in vitro using transcriptome analysis and in vivo in different humanized mice models. CD4LV-FOXP3 T cells express key molecules in common with freshly isolated Treg cells. CD4LV-FOXP3 T cells can significantly extend the survival of xeno GVHD model mice, both in autologous and allogenic conditions and they can suppress xeno GVHD reaction caused by secondary infusion of responder cells. These data indicated CD4LV-FOXP3 T cells have a sustained suppressive function in the various autologous in vivo mice models. In conclusion, we completed the preclinical requirement for the use of the CD4LV-FOXP3 cell product in IPEX Syndrome. The Proof-of-concept trial in a severe monogenic pediatric disease will open to future clinical applications of CD4LV-FOXP3 cell therapy in other autoimmune and immunodysregulatory disorders of different origin.
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Role of human forkhead box P3 in early thymic maturation and peripheral T-cell homeostasis
The Journal of allergy and clinical immunology, 2018Co-Authors: Francesca R. Santoni De Sio, Laura Passerini, Maria Grazia Roncarolo, Matthew H. Porteus, Silvia Restelli, Maria Maddalena Valente, Aleksandar Pramov, Maria Elena Maccari, Francesca Sanvito, Rosa BacchettaAbstract:Background Forkhead box P3 (FOXP3) is a key transcription factor in regulatory T (Treg) cell function. FOXP3 gene mutations cause immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) Syndrome, a fatal autoimmune Syndrome. FOXP3 has also been proposed to act in effector T (Teff) cells, but to date, this role has not been confirmed. Objective We sought to evaluate the effect of reduced FOXP3 expression on human Treg and Teff cell development and correlate it with IPEX Syndrome immune pathology. Methods We developed a model of humanized mice (huMice) in which the human hematopoietic system is stably knocked down or knocked out for the FOXP3 gene (knockdown [KD]/knockout [KO] huMice). Results Because FOXP3-KD/KO was not 100% effective, residual FOXP3 expression in hematopoietic stem progenitor cells was sufficient to give rise to Treg cells with normal expression of FOXP3. However, numerous defects appeared in the Teff cell compartment. Compared with control mice, FOXP3-KD/KO huMice showed altered thymocyte differentiation, with KD/KO thymocytes displaying significantly reduced T-cell receptor (TCR) signaling strength and increased TCR repertoire diversity. Peripheral KD/KO Teff cells were expanded and showed signs of homeostatic proliferation, such as a significantly contracted TCR repertoire, a severely reduced naive compartment, decreased telomeric repeat-binding factor 2 expression, and a skew toward a TH2 profile, resembling an aged immune system. Consistent with results in FOXP3-KD/KO huMice, analysis of patients with IPEX Syndrome provided evidence of defects in the Teff cell compartment at both the thymic and peripheral levels. Conclusions These findings support an intrinsic role for human FOXP3 in controlling thymocyte maturation and peripheral expansion of Teff cells and reveal a previously undescribed pathogenic mechanism through an altered Teff cell compartment in patients with IPEX Syndrome.
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Gene/Cell Therapy Approaches for Immune Dysregulation Polyendocri- nopathy Enteropathy X-Linked Syndrome
2016Co-Authors: Laura Passerini, Matthew H. Porteus, Francesca Santoni R. De Sio, Rosa BacchettaAbstract:Abstract: Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) Syndrome is a rare autoimmune disease due to mutations in the gene encoding for Forkhead box P3 (FOXP3), a transcription factor fundamental for the function of thymus-derived (t) regulatory T (Treg) cells. The dysfunction of Treg cells results in the development of dev-astating autoimmune manifestations affecting multiple organs, eventually leading to premature death in infants, if not promptly treated by hematopoietic stem cell transplantation (HSCT). Novel gene therapy strategies can be developed for IPEX Syndrome as more definitive cure than allogeneic HSCT. Here we describe the therapeutic approaches, alternative to HSCT, currently under development. We described that effector T cells can be converted in regulatory T cells by LV-mediated FOXP3-gene transfer in differentiated T lymphocytes. Despite FOXP3 mutations mainly affect a highly specific T cell subset, manipulation of stem cells could be required for long-term remission of the disease. Therefore, we believe that a more comprehensive strategy should aim at correcting FOXP3-mutated stem cells. Potentials and hurdles of both strategies will be highlighted here
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From IPEX Syndrome to FOXP3 mutation: a lesson on immune dysregulation
Annals of the New York Academy of Sciences, 2016Co-Authors: Rosa Bacchetta, Federica Barzaghi, Maria Grazia RoncaroloAbstract:Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) Syndrome is a rare disorder that increasingly has gained attention as a model of genetic autoimmunity. Numerous papers documenting the key clinical and molecular characteristics of IPEX have provided a detailed understanding of this devastating disease. IPEX is a primary immunodeficiency caused by mutations in the gene FOXP3, which encodes an essential transcription factor required for maintenance of thymus-derived regulatory T (tTreg) cells. tTreg cell dysfunction is the main pathogenic event leading to multiorgan autoimmunity in IPEX. In addition to the traditional clinical presentation (i.e., severe enteropathy, type 1 diabetes, and eczema), IPEX may encompass other variable and distinct clinical manifestations. As IPEX awareness and characterization have increased, so has identification of FOXP3 mutations, with at least 70 to date. Thus, while FOXP3 is the unifying gene, IPEX is a complex and diverse clinical continuum of disorders. Despite understanding IPEX pathogenesis, new treatment options have remained elusive, although early diagnosis led to hematopoietic stem cell transplantation (HSCT) and immunosuppression treatment and improved patient outcomes. Here, we review current knowledge about IPEX Syndrome and highlight findings that could lead to novel targeted treatments.
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Immunodysregulation, Polyendocrinopathy, and Enteropathy, X-Linked (IPEX) Syndrome
Encyclopedia of Immunobiology, 2016Co-Authors: Rosa BacchettaAbstract:Forkhead box protein 3 (FOXP3) is a transcriptional regulator that plays an essential role in the maintenance of self-tolerance and prevention of autoimmune diseases by regulating the function of CD4 + T regulatory cells (Tregs). Thus, X-linked germ line mutations resulting in decrease or loss of FOXP3 protein cause Treg deficiency and result in early-onset and fatal autoimmune disorders collectively called immunodysregulation, polyendocrinopathy, and enteropathy, X-linked (IPEX) Syndrome. Without treatment, IPEX Syndrome can lead to death within the first years of life. We review here the current knowledge on the effects of FOXP3 mutations, the clinical presentation of IPEX Syndrome and its immunological alterations, and how to facilitate a correct diagnosis of the disease in order to timely administer the best available treatment.
Laura Passerini - One of the best experts on this subject based on the ideXlab platform.
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IPEX Syndrome: Improved Knowledge of Immune Pathogenesis Empowers Diagnosis.
Frontiers in pediatrics, 2021Co-Authors: Federica Barzaghi, Laura PasseriniAbstract:Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) Syndrome is a rare monogenic autoimmune disease with variable clinical manifestations, ranging from early-onset severe autoimmunity, including enteropathy, eczema, and type 1 diabetes, to late-onset or atypical symptoms. Despite the clinical heterogeneity, the unifying feature of IPEX is mutation of the FOXP3 gene, which encodes a transcription factor essential for maintenance of thymus-derived regulatory T cells (Tregs). In IPEX patients, Tregs can be present, although unstable and impaired in function, unable to inhibit proliferation and cytokine production of effector T (Teff) cells. Mutated FOXP3 can also disrupt other compartments: FOXP3-deficient Teff cells proliferate more than the wild-type counterpart, display altered T-cell-receptor signaling response, a reduced T-naive compartment and a skew toward a Th2 profile. Due to FOXP3 mutations, the frequency of autoreactive B cells is increased and the IgA and IgE production is altered, together with early emergence of tissue-specific autoantibodies. Recently, the awareness of the wide clinical spectrum of IPEX improved the diagnostic tools. In cases presenting with enteropathy, histological evaluation is helpful, although there are no pathognomonic signs of disease. On the other hand, the study of FOXP3 expression and in vitro Treg function, as well as the detection of specific circulating autoantibodies, is recommended to narrow the differential diagnosis. Nowadays, Sanger sequencing should be limited to cases presenting with the classical triad of symptoms; otherwise, next-generation sequencing is recommended, given the cost-effectiveness and the advantage of excluding IPEX-like Syndromes. The latter approach could be time spearing in children with severe phenotypes and candidate to advanced therapies.
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Treatment with rapamycin can restore regulatory T-cell function in IPEX patients.
The Journal of allergy and clinical immunology, 2019Co-Authors: Laura Passerini, Federica Barzaghi, Rosalia Curto, Claudia Sartirana, Graziano Barera, Francesca Tucci, Luca Albarello, Alberto Mariani, Pier Alberto Testoni, Elena BazzigaluppiAbstract:Background Immune-dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) Syndrome is a lethal disease caused by mutations in a transcription factor critical for the function of thymus-derived regulatory T (Treg) cells (ie, FOXP3), resulting in impaired Treg function and autoimmunity. At present, hematopoietic stem cell transplantation is the therapy of choice for patients with IPEX Syndrome. If not available, multiple immunosuppressive regimens have been used with poor disease-free survival at long-term follow-up. Rapamycin has been shown to suppress peripheral T cells while sparing Treg cells expressing wild-type FOXP3, thereby proving beneficial in the clinical setting of immune dysregulation. However, the mechanisms of immunosuppression selective to Treg cells in patients with IPEX Syndrome are unclear. Objective We sought to determine the cellular and molecular basis of the clinical benefit observed under rapamycin treatment in 6 patients with IPEX Syndrome with different FOXP3 mutations. Methods Phenotype and function of FOXP3-mutated Treg cells from rapamycin-treated patients with IPEX Syndrome were tested by flow cytometry and in vitro suppression assays, and the gene expression profile of rapamycin-conditioned Treg cells by droplet-digital PCR. Results Clinical and histologic improvements in patients correlated with partially restored Treg function, independent of FOXP3 expression or Treg frequency. Expression of TNF-receptor-superfamily-member 18 (TNFRSF18, glucocorticoid-induced TNF-receptor–related) and EBV-induced-3 (EBI3, an IL-35 subunit) in patients' Treg cells increased during treatment as compared with that of Treg cells from untreated healthy subjects. Furthermore inhibition of glucocorticoid-induced TNF-receptor–related and Ebi3 partially reverted in vitro suppression by in vivo rapamycin-conditioned Treg cells. Conclusions Rapamycin is able to affect Treg suppressive function via a FOXP3-independent mechanism, thus sustaining the clinical improvement observed in patients with IPEX Syndrome under rapamycin treatment.
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Immunoregulatory cell therapy with lentiviral-mediated FOXP3 converted CD4+ T cells into Treg cells: towards the proof-of-concept application in IPEX Syndrome
Cytotherapy, 2019Co-Authors: Yohei Sato, Maria Grazia Roncarolo, Laura Passerini, Rosa BacchettaAbstract:Background & Aim FOXP3 is an essential transcription factor for the regulatory T cell (Treg) function and therefore is a key regulator for the tolerance maintenance. Treg cell therapy, either with freshly isolated or expanded in vitro, has been proven to be safe but still challenging because of difficulties in isolating sufficient number of pure Treg cells, stability of the expanded preparations and Treg plasticity in vivo under pro-inflammatory conditions. The key role of FOXP3 and Treg cells in immune function is exemplified by immune dysregulation, polyendocrinopathy, enteropathy, X-linked Syndrome (IPEX), a monogenic primary immune regulatory disease caused by mutations in FOXP3, that lead to impaired Treg cell function and early onset autoimmune manifestations. Our recent international retrospective study demonstrated suboptimal disease-free survival from current therapeutic options such as immunosuppression and allogeneic hematopoietic stem cell transplantation. Therefore, there is a great unmet medical need in patients with IPEX Syndrome. Methods, Results & Conclusion We investigated lentiviral FOXP3 gene transfer (LV-FOXP3) in CD4+ T cells as an innovative approach to generate in large number stable Treg cells that could provide therapeutic benefit to IPEX patients lacking functional Treg. We have shown that LV-FOXP3 can converts IPEX patients-derived CD4+ effector T cells into Treg-like cells (CD4LV-FOXP3 T cells). To better investigate the safety and efficacy of this approach and to make it suitable for large scale GMP generation of CD4LV-FOXP3 T cells, we optimized the original lentiviral vector and we assessed the phenotype and function of CD4LV-FOXP3 T cells both in vitro using transcriptome analysis and in vivo in different humanized mice models. CD4LV-FOXP3 T cells express key molecules in common with freshly isolated Treg cells. CD4LV-FOXP3 T cells can significantly extend the survival of xeno GVHD model mice, both in autologous and allogenic conditions and they can suppress xeno GVHD reaction caused by secondary infusion of responder cells. These data indicated CD4LV-FOXP3 T cells have a sustained suppressive function in the various autologous in vivo mice models. In conclusion, we completed the preclinical requirement for the use of the CD4LV-FOXP3 cell product in IPEX Syndrome. The Proof-of-concept trial in a severe monogenic pediatric disease will open to future clinical applications of CD4LV-FOXP3 cell therapy in other autoimmune and immunodysregulatory disorders of different origin.
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Role of human forkhead box P3 in early thymic maturation and peripheral T-cell homeostasis
The Journal of allergy and clinical immunology, 2018Co-Authors: Francesca R. Santoni De Sio, Laura Passerini, Maria Grazia Roncarolo, Matthew H. Porteus, Silvia Restelli, Maria Maddalena Valente, Aleksandar Pramov, Maria Elena Maccari, Francesca Sanvito, Rosa BacchettaAbstract:Background Forkhead box P3 (FOXP3) is a key transcription factor in regulatory T (Treg) cell function. FOXP3 gene mutations cause immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) Syndrome, a fatal autoimmune Syndrome. FOXP3 has also been proposed to act in effector T (Teff) cells, but to date, this role has not been confirmed. Objective We sought to evaluate the effect of reduced FOXP3 expression on human Treg and Teff cell development and correlate it with IPEX Syndrome immune pathology. Methods We developed a model of humanized mice (huMice) in which the human hematopoietic system is stably knocked down or knocked out for the FOXP3 gene (knockdown [KD]/knockout [KO] huMice). Results Because FOXP3-KD/KO was not 100% effective, residual FOXP3 expression in hematopoietic stem progenitor cells was sufficient to give rise to Treg cells with normal expression of FOXP3. However, numerous defects appeared in the Teff cell compartment. Compared with control mice, FOXP3-KD/KO huMice showed altered thymocyte differentiation, with KD/KO thymocytes displaying significantly reduced T-cell receptor (TCR) signaling strength and increased TCR repertoire diversity. Peripheral KD/KO Teff cells were expanded and showed signs of homeostatic proliferation, such as a significantly contracted TCR repertoire, a severely reduced naive compartment, decreased telomeric repeat-binding factor 2 expression, and a skew toward a TH2 profile, resembling an aged immune system. Consistent with results in FOXP3-KD/KO huMice, analysis of patients with IPEX Syndrome provided evidence of defects in the Teff cell compartment at both the thymic and peripheral levels. Conclusions These findings support an intrinsic role for human FOXP3 in controlling thymocyte maturation and peripheral expansion of Teff cells and reveal a previously undescribed pathogenic mechanism through an altered Teff cell compartment in patients with IPEX Syndrome.
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Gene/Cell Therapy Approaches for Immune Dysregulation Polyendocri- nopathy Enteropathy X-Linked Syndrome
2016Co-Authors: Laura Passerini, Matthew H. Porteus, Francesca Santoni R. De Sio, Rosa BacchettaAbstract:Abstract: Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) Syndrome is a rare autoimmune disease due to mutations in the gene encoding for Forkhead box P3 (FOXP3), a transcription factor fundamental for the function of thymus-derived (t) regulatory T (Treg) cells. The dysfunction of Treg cells results in the development of dev-astating autoimmune manifestations affecting multiple organs, eventually leading to premature death in infants, if not promptly treated by hematopoietic stem cell transplantation (HSCT). Novel gene therapy strategies can be developed for IPEX Syndrome as more definitive cure than allogeneic HSCT. Here we describe the therapeutic approaches, alternative to HSCT, currently under development. We described that effector T cells can be converted in regulatory T cells by LV-mediated FOXP3-gene transfer in differentiated T lymphocytes. Despite FOXP3 mutations mainly affect a highly specific T cell subset, manipulation of stem cells could be required for long-term remission of the disease. Therefore, we believe that a more comprehensive strategy should aim at correcting FOXP3-mutated stem cells. Potentials and hurdles of both strategies will be highlighted here
Hyunsu Bae - One of the best experts on this subject based on the ideXlab platform.
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curcumin attenuates the scurfy induced immune disorder a model of IPEX Syndrome with inhibiting th1 th2 th17 responses in mice
Phytomedicine, 2017Co-Authors: Gihyun Lee, Hwan-suck Chung, Kyeseok Lee, Hyeonhoon Lee, Minhwan Kim, Hyunsu BaeAbstract:Abstract Background Immunodysregulation polyendocrinopathy enteropathy X-linked Syndrome (IPEX) is a lethal autoimmune disease caused by mutations in the Foxp3 gene scurfin (scurfy). Immunosuppressive therapy for IPEX patients has been generally ineffective and has caused severe side effects, however curcumin has shown immune regulation properties for inflammatory diseases, such as rheumatoid arthritis, psoriasis, and inflammatory bowel diseases without side effects. Objective The aim of this study was to investigate whether curcumin would attenuate symptoms of IPEX in mouse model and would prolong its survival period. Methods C57BL/6 mice were separated into scurfy or wild-type litter mate groups by genotyping, and each group subsequently was separated into 2 subgroups that were fed a 1% curcumin containing or normal diet from the last day of breast-feeding. After weaning, pups were fed either a 1% curcumin containing or normal diet until all scurfy mice die for survival data. To elucidate immune cell proportions in spleen and lymph nodes, cells were analyzed by flowcytometry. Cellular cytokine production was accessed to investigate the effects of curcumin in T cell differentiation in vitro. Results Scurfy mice fed a 1% curcumin diet survived 4.0-fold longer compared to scurfy (92.5 days) mice fed a normal diet (23 days). A curcumin diet decreased all of the Th1/Th2/Th17 cell populations and attenuated diverse symptoms such as splenomegaly in scurfy mice. In vitro experiments showed that curcumin treatment directly decreased the Th1/Th2/Th17 cytokine production of IFN-γ, IL-4, and IL-17A in CD4+ T cells. Conclusions Curcumin diet attenuated the scurfy-induced immune disorder, a model of IPEX Syndrome, by inhibiting Th1/Th2/Th17 responses in mice. These results have implications for improving clinical therapy for patients with IPEX and other T cell related autoimmune diseases.
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Curcumin attenuates the scurfy-induced immune disorder, a model of IPEX Syndrome, with inhibiting Th1/Th2/Th17 responses in mice.
Phytomedicine : international journal of phytotherapy and phytopharmacology, 2017Co-Authors: Gihyun Lee, Hwan-suck Chung, Kyeseok Lee, Hyeonhoon Lee, Minhwan Kim, Hyunsu BaeAbstract:Abstract Background Immunodysregulation polyendocrinopathy enteropathy X-linked Syndrome (IPEX) is a lethal autoimmune disease caused by mutations in the Foxp3 gene scurfin (scurfy). Immunosuppressive therapy for IPEX patients has been generally ineffective and has caused severe side effects, however curcumin has shown immune regulation properties for inflammatory diseases, such as rheumatoid arthritis, psoriasis, and inflammatory bowel diseases without side effects. Objective The aim of this study was to investigate whether curcumin would attenuate symptoms of IPEX in mouse model and would prolong its survival period. Methods C57BL/6 mice were separated into scurfy or wild-type litter mate groups by genotyping, and each group subsequently was separated into 2 subgroups that were fed a 1% curcumin containing or normal diet from the last day of breast-feeding. After weaning, pups were fed either a 1% curcumin containing or normal diet until all scurfy mice die for survival data. To elucidate immune cell proportions in spleen and lymph nodes, cells were analyzed by flowcytometry. Cellular cytokine production was accessed to investigate the effects of curcumin in T cell differentiation in vitro. Results Scurfy mice fed a 1% curcumin diet survived 4.0-fold longer compared to scurfy (92.5 days) mice fed a normal diet (23 days). A curcumin diet decreased all of the Th1/Th2/Th17 cell populations and attenuated diverse symptoms such as splenomegaly in scurfy mice. In vitro experiments showed that curcumin treatment directly decreased the Th1/Th2/Th17 cytokine production of IFN-γ, IL-4, and IL-17A in CD4+ T cells. Conclusions Curcumin diet attenuated the scurfy-induced immune disorder, a model of IPEX Syndrome, by inhibiting Th1/Th2/Th17 responses in mice. These results have implications for improving clinical therapy for patients with IPEX and other T cell related autoimmune diseases.
Brandt Groh - One of the best experts on this subject based on the ideXlab platform.
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Epstein Barr virus induced lymphoma in a child with IPEX Syndrome.
Pediatric blood & cancer, 2007Co-Authors: Kenneth G. Lucas, David Ungar, Melanie Comito, Brandt GrohAbstract:IPEX Syndrome (immune deficiency, polyendocrinopathy, enteropathy, X-linked) is a disorder or regulatory T cell (Treg) function which can result in early death due to infection or complications related to autoimmunity. Therapeutic options for these patients can include allogeneic stem cell transplantation (SCT) or the use of immunosuppressive regimens to control the manifestations of autoimmunity. We report a patient with IPEX Syndrome who was managed with rapamycin and subsequently developed EBV induced lymphoma. Pediatr Blood Cancer 2008;50:1056–1057. © 2007 Wiley-Liss, Inc.
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Submyeloablative cord blood transplantation corrects clinical defects seen in IPEX Syndrome
Bone marrow transplantation, 2006Co-Authors: Kenneth G. Lucas, David Ungar, Melanie Comito, Michael G. Bayerl, Brandt GrohAbstract:Submyeloablative cord blood transplantation corrects clinical defects seen in IPEX Syndrome
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Submyeloablative Cord Blood Transplant Corrects Clinical Defects Seen in IPEX Syndrome.
Blood, 2006Co-Authors: Kenneth G. Lucas, Melanie Comito, David R. Ungar, Brandt GrohAbstract:IPEX Syndrome (immune dysfunction, polyendocrinopathy, enteropathy, X-linked) is a disorder of regulatory T cell function caused by mutations in the FOXP3 gene. This disorder is generally associated with a fatal outcome early in life from complications related to bleeding, infection, or enteritis. Allogeneic stem cell transplant (SCT) can be curative for this disorder, but pre-transplant disease-related complications may preclude a full myeloablative conditioning regimen. We report a seven year old boy with IPEX whose pre-transplant course was complicated by recurrent laryngeal papillomas and severe airway obstruction, frequent pulmonary infections, and recurrent gastrointestinal hemorrhage. Due to these problems he underwent a submyeloablative conditioning regimen consisting of fludarabine 30 mg/m2/day for 6 days, Busulfan 0.8 mg/kg/dose every 6 hours for 2 days, then anti-thymocyte globulin 2.5 mg/kg/dose for 4 days. Mycophenylate and cyclosporine were used for graft versus host disease (GVHD) prophylaxis. This patient received an HLA 5/6 matched (A,B,DR) unrelated donor cord blood transplant with 1.1 ×10 8 total nucleated cells/kg and 3 × 10 5 CD34+ cells/kg. His diarrhea and airway issues resolved following the conditioning regimen. The patient achieved myeloid engraftment on day 14, and was platelet and red cell transfusion independent by day 29 and 56, respectively. He had 81% and 98% donor chimerism at 2 and 9 months post-transplant, respectively. While tapering cylcosporine he developed graft versus host disease of the lower GI tract, which was sucessfully treated with a course of corticosteroids. He also experienced reactivation of EBV and was treated with 4 weekly doses (375 mg/m2) of anti-CD20 monoclonal antibody. This patient has had full resolution of his clinical symptoms and is currently 17 months post-transplant, with no signs of GVHD. For those children who do not respond or have only partial improvement following immunosuppressive therapy, allogeneic SCT using a submyeloablative approach can be well tolerated and result in sustained donor chimerism.
Eleonora Gambineri - One of the best experts on this subject based on the ideXlab platform.
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Clinical, Immunological, and Molecular Heterogeneity of 173 Patients With the Phenotype of Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked (IPEX) Syndrome.
Frontiers in immunology, 2018Co-Authors: Eleonora Gambineri, Sara Ciullini Mannurita, Stephanie Anover-sombke, David Hagin, Marina Vignoli, Stacey Deboer, Gesmar Rodrigues Silva Segundo, Eric J. Allenspach, Claudio Favre, Hans D. OchsAbstract:Background: Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) Syndrome is a rare recessive disorder caused by mutations in the FOXP3 gene. In addition, there has been an increasing number of patients with wild-type FOXP3 gene and, in some cases, mutations in other immune regulatory genes. Objective: To molecularly asses a cohort of 173 patients with the IPEX phenotype and to delineate the relationship between the clinical/immunologic phenotypes and the genotypes. Methods: We reviewed the clinical presentation and laboratory characteristics of each patient and compared clinical and laboratory data of FOXP3 mutation-positive (IPEX patients) with those from FOXP3 mutation-negative patients (IPEX-like). A total of 173 affected patients underwent direct sequence analysis of the FOXP3 gene while 85 IPEX-like patients with normal FOXP3 were investigated by a multiplex panel of "Primary Immune Deficiency (PID-related) genes." Results: Forty-four distinct FOXP3 variants were identified in 88 IPEX patients, 9 of which were not previously reported. Among the 85 IPEX-like patients, 19 different disease-associated variants affecting 9 distinct genes were identified. Conclusions: We provide a comprehensive analysis of the clinical features and molecular bases of IPEX and IPEX-like patients. Although we were not able to identify major distinctive clinical features to differentiate IPEX from IPEX-like Syndromes, we propose a simple flow-chart to effectively evaluate such patients and to focus on the most likely molecular diagnosis. Given the large number of potential candidate genes and overlapping phenotypes, selecting a panel of PID-related genes will facilitate a molecular diagnosis.
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Proteomics plus genomics approaches in primary immunodeficiency: the case of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) Syndrome
Clinical and experimental immunology, 2011Co-Authors: Danila Zennaro, Eleonora Gambineri, Enrico Scala, D. Pomponi, Elisabetta Caprini, Diego Arcelli, Giandomenico Russo, Adriano MariAbstract:Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) is a rare Syndrome due to a mutation in the forkhead box protein 3 gene (FOXP3) leading to an impaired regulatory T cell (T(reg) ) activity associated both with skewed T helper type 2 (Th2) response and autoreactive phenomena. The purpose of this study was to describe a combined proteomics and genomics approach to comprehensively evaluate clinical and immunological phenotypes of patients affected by IPEX. T cell receptor (TCR)-Vβ repertoire and peripheral blood lymphocytes phenotype from three brothers affected by IPEX were studied by flow cytometry. Specific immunoglobulin (Ig)E were evaluated by means of an allergenic molecules microarray [immuno solid-phase allergen chip (ISAC)]. Total RNA was extracted and hybridized to Affymetrix oligonucleotide arrays to obtain quantitative gene-expression levels. No FOXP3 protein was detectable within CD127(-) CD25(high) CD4(+) T cells from peripheral blood. A T cell-naive phenotype (CD62L(+) CD45R0(-)) associated with a reduction of both CD26 and CD7 expression and a TCR-Vβ 8 and 22 family expansions were found. B lymphocytes were mainly CD5(+) (B1) cells expressing a naive phenotype (tcl1(+) CD27(-)). The three IPEX patients had severe food allergy and specific IgE reactivity to cow's milk allergens, a hen's egg allergen and a wheat allergen. Gene expression profile analysis revealed a dysregulation associated mainly with Th1/Th2 pathways. The multiplexing evaluation reported in this study represents a comprehensive approach in the assessment of genetic conditions affecting the immune system such as the IPEX Syndrome, paving the way for the development of diagnostic tools to improve the standard clinical and immunological profiling of the disease.
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Functional type 1 regulatory T cells develop regardless of FOXP3 mutations in patients with IPEX Syndrome
European journal of immunology, 2011Co-Authors: Laura Passerini, Markus G Seidel, Eleonora Gambineri, Sara Di Nunzio, Silvia Gregori, Massimiliano Cecconi, Giantonio Cazzola, Lucia Perroni, Alberto Tommasini, Silvia VignolaAbstract:Mutations of forkhead box p3 (FOXP3), the master gene for naturally occurring regulatory T cells (nTregs), are responsible for the impaired function of nTregs, resulting in an autoimmune disease known as the immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) Syndrome. The relevance of other peripheral tolerance mechanisms, such as the presence and function of type 1 regulatory T (Tr1) cells, the major adaptive IL-10-producing Treg subset, in patients with IPEX Syndrome remains to be clarified. FOXP3mutated Tr1-polarized cells, differentiated in vitro from CD4+ T cells of four IPEX patients, were enriched in IL-10+IL-4−IFN-γ+ T cells, a cytokine production profile specific for Tr1 cells, and expressed low levels of FOXP3 and high levels of Granzyme-B. IPEX Tr1 cells were hypoproliferative and suppressive, thus indicating that FOXP3 mutations did not impair their function. Furthermore, we isolated Tr1 cell clones from the peripheral blood of one FOXP3null patient, demonstrating that Tr1 cells are present in vivo and they can be expanded in vitro in the absence of WT FOXP3. Overall, our results (i) show that functional Tr1 cells differentiate independently of FOXP3, (ii) confirm that human Tr1 and nTregs are distinct T-cell lineages, and (iii) suggest that under favorable conditions Tr1 cells could exert regulatory functions in IPEX patients.
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The spectrum of autoantibodies in IPEX Syndrome is broad and includes anti-mitochondrial autoantibodies
Journal of autoimmunity, 2010Co-Authors: Masanobu Tsuda, Troy R Torgerson, Carlo Selmi, Eleonora Gambineri, Magda Carneiro-sampaio, Sara Ciullini Mannurita, Patrick S.c. Leung, Gary L. Norman, M. Eric GershwinAbstract:IPEX Syndrome is a congenital disorder of immune regulation caused by mutations in the FOXP3 gene, which is required for the suppressive function of naturally arising CD4 + CD25 + regulatory T cells. In this case series we evaluated serum samples from 12 patients with IPEX Syndrome for the presence of common autoantibodies associated with a broad range of autoimmune disorders. We note that 75% of patients (9/12) had 1 or more autoantibodies, an incidence far above the cumulative rate observed in the general population. The range of autoantibodies differed between patients and there was no predominant autoantibody or pattern of autoantibodies present in this cohort. Surprisingly, one patient had high-titer anti-mitochondrial antibodies (AMA) typically associated with primary biliary cirrhosis (PBC) although the patient had no signs of cholestasis. PBC is a well-characterized autoimmune disease that occurs primarily in women and includes the serological hallmarks of serum AMA and elevated IgM which were both present in this patient. PBC is virtually absent in children with the exception of one reported child with interleukin 2 receptor α (CD25) deficiency which is associated with an IPEX-like regulatory T cell dysfunction. Based on the present data and the available literature we suggest a direct role for CD4 + CD25 + regulatory T cells in restraining B cell autoantibody production and that defects in regulatory T cells may be crucial to the development of PBC.
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S2012 Novel Mutations and Clinical Features in Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked (IPEX) Syndrome
Gastroenterology, 2010Co-Authors: Crystal Knight, Hans D. Ochs, Eleonora Gambineri, Mary J. Hackett, Stephanie Anover-sombke, Troy R TorgersonAbstract:IPEX Syndrome is a rare disorder presenting in the first few months of life and characterized by a triad of severe autoimmune enteropathy (AIE), endocrinopathy (usually Type I diabetes or thyroiditis), and dermatitis. In addition, patients frequently present with other autoimmune phenomena including hemolytic anemia, thrombocytopenia, neutropenia, hepatitis, and glomerulonephropathy. The disease has been linked to mutations in the FOXP3 gene, located on the X-chromosome (Xp11.23-Xp13.3). FOXP3 encodes a 48-kD protein that is a member of the forkhead/winged-helix family of transcription factors and is essential for development of CD4+CD25+ regulatory T-cells. We have evaluated a large cohort of patients with IPEX symptoms who were referred to our lab for FOXP3 gene sequencing. In this cohort, we have identified 26 different pathogenic FOXP3 mutations in 39 families. In addition, we have identified 2 mutations that are likely non-pathogenic, as they have been found in unaffected family members, or have been identified in the general population. We have also collected a large cohort of patients with the IPEX phenotype, who do not have a FOXP3 mutation and are therefore “IPEX-like”. Combining our mutations with those reported by others in the literature, there are now a total of 55 FOXP3 mutations identified in 84 families with IPEX Syndrome. Of these, 16 are splicingmutations, 26missense, 8 frameshift (including 1 premature ATG, 2 alternative ATG, and 1 premature termination), 2 in-frame deletions, 1 complex(insertion/deletion/frameshift), and 2 polyadenylation site mutations. The majority of mutations are located in the forkhead DNA-binding domain of the protein (26/55 exons 9-11). The two most common mutations are a missense mutation in exon 11 (c.1150G>A) resulting in an Ala to Thr substitution at residue 384 (p.A384T) and a 3 nucleotide inframe deletion in Exon 7 leading to a single amino acid deletion (p.251del) in the leucine zipper. These mutations were found in 11 and 6 families respectively. The remainder of the mutations are equally distributed throughout the gene and affect all exons and include mutations in other important functional domains including the upstream proline-rich region (exon 1-4) and the leucine-zipper (exons 6-7). We also describe some basic genotypephenotype correlations that are beginning to emerge as a result of the identification of more FOXP3 genemutations in IPEX.We believe that by increasing our knowledge of the molecular basis of IPEX Syndrome we will better understand how specific FOXP3 mutations impact regulatory T cell development which will aid our understanding of autoimmune diseases in general.