Rao, A. et al. Successful bone marrow transplantation for IPEX syndrome after reduced-intensity conditioning. Blood 109, 383-385

Washington University in St. Louis, San Luis, Missouri, United States
Blood (Impact Factor: 10.45). 02/2007; 109(1):383-5. DOI: 10.1182/blood-2006-05-025072
Source: PubMed


Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare, fatal autoimmune disorder caused by mutations in the FOXP3 gene leading to the disruption of signaling pathways involved in regulatory T-lymphocyte function. Lifelong multiagent immunosuppression is necessary to control debilitating autoimmune manifestations such as colitis and food allergies. Allogeneic hematopoietic stem cell transplantation (HSCT) can restore T-cell regulatory function but has been previously associated with poor outcome. We describe successful HSCT in 4 patients with IPEX syndrome using a novel reduced-intensity conditioning regimen that resulted in stable donor engraftment, reconstitution of FOXP3+ T regulatory CD4+ cells, and amelioration of gastrointestinal symptoms.

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Available from: Jignesh Dalal, Oct 09, 2015
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    • "Treg cells increased for up to 90 days in hematopoietic stem cell transplantation patients as well as in IPEX syndrome patients after alemtuzumab treatment [26] [27] [28]. In renal transplantation in adults, alemtuzumab was able to increase the percentage of CD4 "
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    ABSTRACT: T regulatory cells (Tregs) play a critical role in the immunologic tolerance to the graft in transplantation. Thus, due to their immunosuppressive capability, ex vivo expanded Tregs may be used as a cellular therapy and an attractive novel strategy to control chronic rejection and eliminate need for lifelong pharmacological immunosuppression. Since Treg therapy is still in its infancy, initially Tregs still need to be applied in combination with pharmacological agents to prevent rejection. Fortunately, some of the medications have been shown to enhance the function and number of Tregs. In the clinic, different immunosuppressive regimens are used for individual patients for different types of organ transplantation. In this review, we present the most commonly used pharmacological agents for immunosuppression and discuss how they affect the Treg population. It is extremely difficult to dissect the effect of single agent on Tregs population in clinical settings since usually the combination of several medications is applied at the same time for graft protection. Nevertheless, experimental and clinical data indicate that thymoglobulin as immunosuppressive induction and mTOR inhibitors as immunosuppressive maintenance agents have the most beneficial effect on Treg population in the blood. Among supplemental agents promoting Tregs, anti-TNFα preparations have been in clinical use (in autoimmune diseases) for many years, so they are optimal candidates for testing in transplant settings in combination with Treg based cellular therapy.
    International immunopharmacology 03/2013; 16(3). DOI:10.1016/j.intimp.2013.02.015 · 2.47 Impact Factor
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    • "Dermatitis can be eczematiform (mainly atopic dermatitis) (Wildin et al., 2002; Owen et al., 2003; Ruemmele et al., 2008), ichthyosiform (Baud et al., 2001; Rao et al., 2007), psoriasiform (Nieves et al., 2004; De Benedetti et al., 2006), or any combination of the above (e.g., atopic dermatitis and psoriasis coexisting on different areas of the skin) (Halabi-Tawil et al., 2009). Skin involvement is severe and diffuse, characterized by erythematous exudative plaques that could evolve into more lichenfied plaques (Halabi-Tawil et al., 2009). "
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    ABSTRACT: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare monogenic primary immunodeficiency (PID) due to mutations of FOXP3, a key transcription factor for naturally occurring (n) regulatory T (Treg) cells. The dysfunction of Treg cells is the main pathogenic event leading to the multi-organ autoimmunity that characterizes IPEX syndrome, a paradigm of genetically determined PID with autoimmunity. IPEX has a severe early onset and can become rapidly fatal within the first year of life regardless of the type and site of the mutation. The initial presenting symptoms are severe enteritis and/or type-1 diabetes mellitus, alone or in combination with eczema and elevated serum IgE. Other autoimmune symptoms, such as hypothyroidism, cytopenia, hepatitis, nephropathy, arthritis, and alopecia can develop in patients who survive the initial acute phase. The current therapeutic options for IPEX patients are limited. Supportive and replacement therapies combined with pharmacological immunosuppression are required to control symptoms at onset. However, these procedures can allow only a reduction of the clinical manifestations without a permanent control of the disease. The only known effective cure for IPEX syndrome is hematopoietic stem cell transplantation, but it is always limited by the availability of a suitable donor and the lack of specific guidelines for bone marrow transplant in the context of this disease. This review aims to summarize the clinical histories and genomic mutations of the IPEX patients described in the literature to date. We will focus on the clinical and immunological features that allow differential diagnosis of IPEX syndrome and distinguish it from other PID with autoimmunity. The efficacy of the current therapies will be reviewed, and possible innovative approaches, based on the latest highlights of the pathogenesis to treat this severe primary autoimmune disease of childhood, will be discussed.
    Frontiers in Immunology 07/2012; 3:211. DOI:10.3389/fimmu.2012.00211
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    • "Immunosuppressive agents that target T-cell activation used either alone or in combination with steroids have a beneficiary effect but do not permit long-term remission and ultimately fail due to toxicity or increased infection susceptibility. Bone marrow transplantation is so far the only hope of a curative treatment (Rao et al., 2007). As for many recessive X-linked diseases, prenatal diagnosis was first based on sex selection followed by the termination of male fetuses. "
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    ABSTRACT: Molecular diagnosis and prenatal care of two pregnant women at risk of transmitting immunodysregulation, polyendocrinopathy, enteropathy X-linked (IPEX) syndrome. FOXP3 coding sequence and exon boundaries were analyzed in the two consultants and family members. Non-invasive sex determination and specific prenatal diagnosis was realized. Following sequence analysis a new FOXP3 mutation was identified in each consultant. Sex diagnosis realized by amplification of Y sequences from the plasma of the two mothers revealed a male and a female fetus, respectively. Prenatal diagnosis showed that the male fetus was unaffected. The baby is now born and healthy. Subsequent ultrasound examinations confirmed the sex in the second pregnancy but unfortunately led to the diagnosis of a 69,XXX triploidy. The pregnancy was thus interrupted. Two new FOXP3 mutations were identified and prenatal diagnosis could be proposed. Due to the rarity of the disease, clinical diagnosis is often considered with delay. Both patients reported here were already pregnant at the beginning of the genetic investigation and one had previously interrupted a male pregnancy for lack of diagnosis. When faced with children with severe refractory diarrhea, clinicians should entertain the possibility of IPEX.
    Prenatal Diagnosis 11/2010; 30(11):1072-8. DOI:10.1002/pd.2613 · 3.27 Impact Factor
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