Autoimmune enteropathy and hepatitis in pediatric heart transplant recipient

AIE is a rare disorder in children that presents with severe diarrhea and malabsorption, caused by immune‐mediated damage to intestinal mucosa. AIE is often associated with various syndromes of immunodeficiency including IPEX syndrome (immune dysregulation, polyendocrinopathy and enteropathy, X‐linked). Dysfunctional T regulatory cells are the source of pathology in both IPEX syndrome and AIE as they are essential in maintaining tolerance to self‐antigens and eliminating autoreactive B cells. This case report describes a 10‐year‐old cardiac transplant and total thymectomy patient on chronic immunosuppression with tacrolimus that presented with AIE and extraintestinal manifestations of cyclical hepatitis. Transition from tacrolimus to sirolimus successfully increased T regulatory cells and resolved enteritis and hepatitis symptoms. Data support that thymectomy at <1 year of age increases risk of autoimmune disease due to abnormal immune maturation. Studies suggest that the sirolimus promotes the upregulation of the FoxP3 protein that is classically associated with Tregs. In turn, Tregs prevent the maturation of autoreactive B cells that lead to autoimmune reactions.     

Hematopoietic stem cell transplantation recovers insulin deficiency in type 1 diabetes mellitus associated with IPEX syndrome

Immune dysregulation, polyendocrinopathy, enteropathy, and X‐linked (IPEX) syndrome is an autoimmune disorder caused by the dysfunction of FOXP3, which leads to regulatory T‐(Treg) cell dysfunction and subsequently autoimmunity including type 1 diabetes mellitus (T1D). Presently, allogeneic hematopoietic stem cell transplantation (HSCT) is a potential curative therapy for IPEX syndrome, but not for T1D. Generally, after complete loss of pancreatic β‐cells, HSCT cannot improve the prognosis of T1D. Here, we report the case of a 16‐year‐old adolescent with late‐onset of FOXP3 R347H mutation associated IPEX syndrome with T1D, where insulin dependency was ameliorated following HSCT. This patient with insulin‐dependent diabetes mellitus required insulin dosage of 1.28 U/kg/day for 1 month before HSCT. Although the results of glucose homeostasis before HSCT revealed impaired insulin secretion and low ΔC‐peptide immunoreactivity (CPR, 1.0 ng/mL), the patient withdrew insulin infusion and remained euglycemic at 15 months after HSCT, and had normal β‐cell function with improved ΔCPR (3.4 ng/mL) at 20 months after HSCT. The present case suggests that HSCT for T1D‐associated IPEX syndrome improves Treg deficiency and prevents elimination of β‐cells. We speculate that the period from the onset of T1D to HSCT could affect the therapeutic efficacy for T1D with IPEX, and early intervention with HSCT before or immediately after the onset of DM can rescue β‐cells and remit T1D completely. Our study elaborates not only the therapeutic strategy for T1D with IPEX, but also the pathogenic mechanism in general T1D.     

X连锁多内分泌腺病肠病伴免疫失调综合征一例基因及蛋白表达研究

目的 探讨表现为顽固性腹泻、皮疹以及有或无胰岛素依赖性糖尿病的疑似X连锁多内分泌腺病肠病伴免疫失调综合征(IPEX)患儿FOXP3基因变异及其蛋白表达水平.方法 对近两年来我院收治的4例表现为早发性顽固性腹泻、皮疹以及有或无胰岛素依赖性糖尿病的疑似IPEX男性患儿进行FOXP3基因扩增及测序分析,将发现的可疑突变位点通过数据库查询及与100例健康儿童相同位点序列比较,采用流式细胞仪检测CD4~+CD25~+FOXP3~+调节性T细胞比例和FOXP3蛋白表达.结果 4例疑似患儿中发现1例FOXP3突变,为11号外显子66位碱基错义突变(G>A),导致FOXP3蛋白370位氨基酸由甲硫氨酸替换为异亮氨酸(Met370Ile),患儿母亲为携带者.100例正常儿童FOXP3基因相同位点未见变异,故可排除该位点多态性可能.该突变为此前未见报道的新突变,患儿CD4~+CD25~+FOXP3~+调节性T细胞比例升高而FOXP3表达量无减低.结论 通过临床、免疫学筛查和基因分析,发现我国首例IPEX患儿(g:13128 G>A c:1298 G>A Met370Ile),对早发胰岛素依赖性糖尿病、顽固性腹泻及不明肾脏损害婴幼儿,应考虑IPEX可能并进行FOXP3基因分析.     

造血干细胞移植治疗Wiskott-Aldrich综合征一例报告及文献复习

目的 Wiskott-Aldrich综合征(WAS)是一种原发性免疫缺陷性疾病,严重病例预后不良.采用人类白细胞抗原(HLA)全相合的同胞骨髓移植成功治疗1例,特此总结并进行文献复习.方法 采用流式细胞仪检测WAS蛋白(WASP)表达和基因分析确诊WAS.患儿姐姐为人类白细胞抗原全相合骨髓供者,所采集骨髓单个核细胞数为4.38×108/kg,CD34+细胞3.78×106/kg患儿体重.采用白消安/环磷酰胺全清髓的预处理方案,环孢菌素单用预防移植物抗宿主病.移植后检测WASP表达和短串联重复序列(STR)作为植入证据.结果 患儿诊断:WAS,WASP(-IVS9+2T>C,WASP阴性).白消安/环磷酰胺预处理后骨髓回输;移植13 d中性粒细胞(ANC)绝对值0.8×109/L,移植15 d起血小板>50×109/L,1个月后正常.移植50 d起患儿WASP表达阳性,STR显示为供者DNA完全嵌合;随访至移植后510 d,患儿健康,WASP稳定表达.结论 结合病例和文献复习,人类白细胞抗原相合同胞骨髓移植治疗典型WAS近期预后较好.     

Development of hemolytic paroxysmal nocturnal hemoglobinuria without graft loss following hematopoietic stem cell transplantation for acquired aplastic anemia

PNH is the most common clonal hematopoietic disorder arising in patients with aAA. PNH is caused by mutations in PIGA, a gene that encodes the catalytic subunit of an enzyme involved in the biosynthesis of GPI anchors, transmembrane glycolipids required for cell surface expression of many proteins. PNH clones likely arise as immune escape mechanisms in aAA by preventing CD1D‐restricted T‐cell recognition of GPI anchors and GPI‐linked autoantigens. Though many patients with aAA treated with IST will develop subclinical PNH clones, only a subset will develop PNH disease, characterized by increased thrombosis, intravascular hemolysis, and potential for severe organ dysfunction. In contrast to IST, allogeneic HSCT for patients with aAA is thought to cure bone marrow aplasia and prevent hematopoietic clonal evolution to PNH. Herein, we present a phenomenon of host‐derived PNH disease arising in a patient with aAA many years following MSD‐BMT, highlighting the importance of monitoring for this clonal disease in aAA patients with stable mixed donor/recipient chimerism after HSCT. We also provide a literature review for similar occurrences of PNH arising after HSCT.     

Contribution of B7RP‐1/ICOS co‐stimulation to lethal acute GVHD

Fujimura J, Takeda K, Kaduka Y, Saito M, Akiba H, Yagita H, Yamashiro Y, Shimizu T, Okumura K. Contribution of B7RP‐1/ICOS co‐stimulation to lethal acute GVHD.
Pediatr Transplantation 2010: 14:540–548. © 2010 John Wiley & Sons A/S. Abstract: Co‐stimulatory molecules expressed on T cells critically regulate donor T‐cell activation and are implicated in acute GVHD after allogeneic BMT. We here investigated the role of interaction between B7‐related protein‐1 (B7RP‐1) and ICOS in murine acute GVHD model that received T cell‐depleted BM cells and splenocytes. Administration of blocking anti‐B7RP‐1 mAb significantly reduced the lethality and symptoms in acute GVHD. A significant hypo‐responsiveness of splenocytes to host alloantigen was observed in the recipient mice treated with anti‐B7RP‐1 mAb. Moreover, acute GVHD was significantly reduced in the recipients of T cells composed of ICOS‐deficient CD8 T cells and WT CD4 T cells compared with that in the recipients of T cells composed of WT CD8 T cells and ICOS‐deficient CD4 T cells. These results suggested that B7RP‐1/ICOS co‐stimulatory signal plays a role in the activation of alloantigen‐reactive donor T cells, particularly in CD8 T cells, in murine acute GVHD model, and that the blockade of B7RP‐1/ICOS interaction may be useful for selectively manipulating allo‐reactive T cells in the recipients with acute GVHD.     

A potential screening tool for IPEX syndrome.

IPEX syndrome is a rare, inherited condition characterized by immune dysfunction, polyendocrinopathy, enteropathy, and X-linked recessive inheritance. Patients typically present in infancy with severe diarrhea and failure to thrive. Most children die by 1 year of age without therapy. The diagnosis is established by genetic analysis, which often takes several weeks to complete and can sometimes delay crucial immunosuppressive treatment. We attempted to develop a screening tool that allows rapid identification of patients with IPEX syndrome using immunocytochemical staining of FOXP3+ cells in bowel biopsies. We found that 2 patients with classic IPEX syndrome due to protein-truncating mutations in FOXP3 had markedly decreased staining of FOXP3+ T cells in the lamina propria and lymphoid aggregates. One patient with a mild, late-onset presentation and a missense mutation in FOXP3 had intact staining of FOXP3+ cells. This screening test provides a valuable tool for diagnosing IPEX syndrome in extremely ill patients who may not tolerate a delay in therapeutic intervention.     

Hypogammaglobulinemia and reduced numbers of B-cells in children with myelodysplastic syndrome

BACKGROUND: Immunodeficiency in pediatric patients with myelodysplastic syndrome (MDS) has not been described. We report the clinical course of three children with MDS, hypogammaglobulinemia, and reduced numbers of B-cells and B-cell precursors. OBSERVATIONS: Three patients with recurrent infection who were younger than 1-year-old had MDS of the refractory anemia (RA) subtype diagnosed. All had reduced numbers of circulating B-cells and hypogammaglobulinemia. In two patients, cytogenetic studies revealed a monosomy 7 karyotype and bone marrow studies showed decreased numbers of CD34+ progenitor cells and CD 19+ B-cells. Both patients had prolonged courses (7 yrs 10 mos and 6 yrs 9 mos) characterized by recurrent infection and slowly progressive pancytopenia. Both received allogeneic bone marrow transplantation (BMT). The third patient had normal cytogenetic studies and a normal number of CD34+ progenitors but decreased CD19+ B-cells in the bone marrow. She had a stable course with refractory anemia over the course of 7 years. CONCLUSIONS: Pediatric patients with MDS may have hypogammaglobulinemia and reduced numbers of B-cells. These findings do not preclude a relatively stable and prolonged clinical course. Children with newly diagnosed MDS should have an immunologic evaluation in addition to their hematologic assessment.     

Epstein Barr virus induced lymphoma in a child with IPEX syndrome

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.     

Same sibling marrow following cord allogeneic transplantation as therapy for second relapse acute promyelocytic leukemia in a pediatric patient

Optimal therapy for relapsed APL in pediatric patients is controversial. Allogeneic HSCT is an alternative, with event‐free survival of 70–75%. We report a pediatric patient with APL who relapsed 28 months after CBT from her sibling and then was treated with BMT from the same donor. Bone marrow was selected for higher cell dose, donor availability, and partial donor chimerism. Persistent molecular remission was achieved, currently at 65 months after BMT. This case suggests the potential role of GVL activity in APL and illustrates the use of different cell sources from the same donor in allogeneic transplantation for pediatric patients.     

异基因造血干细胞移植治疗儿童重型再生障碍性贫血

目的探讨异基因造血干细胞移植(allo-HSCT)治疗儿童重型再生障碍性贫血(SAA)的疗效及并发症。方法 4例SAA患儿,均接受氟达拉滨、环磷酰胺、抗胸腺细胞球蛋白预处理;其中3例患儿行HLA全相合同胞骨髓造血干细胞移植(BMT),1例患儿行HLA全相合同胞外周血造血干细胞移植(PBSCT)。同胞供者采集重组人粒细胞集落刺激因子5μg.kg-1.d-1,动员骨髓及外周血干细胞。采用环孢素+短疗程小剂量甲氨蝶呤方案预防移植物抗宿主病,前列腺素E预防肝静脉闭塞综合征,更昔洛韦预防巨细胞病毒感染,美司那及水化碱化预防出血性膀胱炎。通过DNA短串联重复序列多态性分析检测植入情况。结果 2例BMT患儿及1例PBSCT患儿完全植入;1例BMT患儿嵌合植入。中性粒细胞>0.5×109L-1中位时间12 d(9～15 d),血小板>20×109L-1中位时间19 d(12～30 d)。结论 allo-HSCT是治疗儿童SAA的有效方法,维持造血功能以及移植后并发症的发生及防治,仍是目前重点讨论的课题。     

Hurler syndrome with severe complication in post-bone marrow transplantation course: Life threatening interstitial pneumonitis and hypertension

Bone marrow transplantation (BMT) was performed in a 3 year old patient with Hurler syndrome. The post-BMT course was complicated by interstitial pneumonitis and severe hypertension, which were life threatening. The patient responded well to therapy and recovered. BMT in this patient resulted in significant clinical improvement in the signs and symptoms of Hurler syndrome. Biochemical improvement, including elevated α-l -iduronidase activity in white blood cells and decreased urinary glycosaminoglycan excretion was significant. However, skeletal and neurological impairment were not improved. We conclude that BMT for Hurler syndrome should be performed at an earlier stage, before severe neuronal damage has occurred. Moreover, BMT is a high risk procedure and there will always be a possibility that life threatening complications will occur, as in our case.     

Clinical and Biochemical Outcome of Marrow Transplantation for Gaucher Disease of the Norrbottnian Type

ABSTRACT. Three children, two girls and one boy, with Gaucher disease of the Norrbottnian type were treated by allogeneic bone marrow transplantation (BMT). Two of the donors were heterozygotes for Gaucher disease, and the third did not carry the gene. Engraftment was achieved in all three children but the boy became a chimera. The children have been followed from 1.5 to 6 years after transplantation. In each case the outcome was favourable, and in two children (patients 1 and 3) the BMT has been life saving. In all three cases a positive biochemical effect was apparent. Almost all biochemical parameters normalized within one year. The authors conclude that BMT is the treatment of choice in severe cases of Gaucher disease. BMT should be considered early in the course of disease and vigorous efforts made to find a suitable donor.     

Identical phenotype in patients with somatic and germline CD95 mutations requires a new diagnostic approach to autoimmune lymphoproliferative syndrome

In a patient with a somatic mutation in the CD95 gene, the long-term evolution of the clinical phenotype was indistinguishable from that of patients with autoimmune lymphoproliferative syndrome caused by germline CD95 mutations. A new diagnostic algorithm for autoimmune lymphoproliferative syndrome is suggested incorporating studies on sorted TCRalpha/beta+CD3+CD8-CD4- T cells.     

Late graft failure in FA – case report and review of the literature

Ehlert K, Groll AH, Rossig C, Fruehwald MC, Juergens H. Late graft failure in FA – case report and review of the literature. Abstract: Hematological disorders in patients with FA can only be cured by allogeneic HSCT. Severe infections in primary and early secondary graft failures pose a particular risk. Whereas most graft failures occur within 100 days, those observed after day +100 are infrequent. Here, we present our analysis of a secondary graft failure more than five yr after a first allogeneic HSCT. In this patient, isolated thrombocytopenia over a period of 12 months resulted in a chimerism subset analysis revealing a considerable decrease in the CD34‐positive donor cell fraction. After a second fludarabine‐based preparative regimen, the patient received PBSC from the same donor. Chimerism returned to full donor in all subsets. This clinical course demonstrates that isolated thrombocytopenia can precede complete graft failure for several months. Our review of the literature on late graft failures in patients with FA after day +100 reveals the absence of fludarabine in the preparative regimen as a potential risk factor. Further clinical research is necessary to identify more suitable approaches for ensuring safe and stable engraftment.     

Clinical and biochemical outcome of marrow transplantation for Gaucher disease of the Norrbottnian type

Three children, two girls and one boy, with Gaucher disease of the Norrbottnian type were treated by allogeneic bone marrow transplantation (BMT). Two of the donors were heterozygotes for Gaucher disease, and the third did not carry the gene. Engraftment was achieved in all three children but the boy became a chimera. The children have been followed from 1.5 to 6 years after transplantation. In each case the outcome was favourable, and in two children (patients 1 and 3) the BMT has been life saving. In all three cases a positive biochemical effect was apparent. Almost all biochemical parameters normalized within one year. The authors conclude that BMT is the treatment of choice in severe cases of Gaucher disease. BMT should be considered early in the course of disease and vigorous efforts made to find a suitable donor.     

Treatment of adrenoleukodystrophy with bone marrow transplantation

Three children with adrenoleukodystrophy (ALD) underwent allogeneic bone marrow transplantation (BMT) between 1992 and 1993. The first boy had attention deficits, marked neuropsychological deficits and widespread demyelination in the frontal lobes on MRI before transplantation. Four years later he has mentally deteriorated and the demyelination on MRI has progressed. The second boy had no symptoms but had white matter lesions on MRI when diagnosed. He was regularly followed with MRI and neuropsychological investigations until BMT 18 months later. A progress of the lesions was noted on the initial MRI investigations, and 4 months before BMT a worsening of deficits in attention and kinaesthetic praxis could be observed. He rapidly deteriorated after the transplantation and died 18 months later. Both PCR and in situ hybridization confirmed the presence of donor cells in the brain. The third boy had no symptoms but white matter lesions on MRI when diagnosed. The neuropsychological tests remained normal but a slight progress was observed on MRI just before transplantation. This boy is still healthy 3.5 years after BMT. BMT as treatment for ALD has to be considered very early, even in a child without symptoms but signs of demyelination on MRI, if a suitable donor is available.     

Successful haploidentical PBSCT with subsequent T‐cell addbacks in a boy with HyperIgM syndrome presenting as severe congenital neutropenia

Jasinska A, Kalwak K, Trelinska J, Borowiec M, Piatosa B, Zeman K, Mlynarski W. Successful haploidentical PBSCT with subsequent T‐cell addbacks in a boy with HyperIgM syndrome presenting as severe congenital neutropenia. Abstract: HIGM syndrome is a group of primary immunodeficiency disorders characterized by recurrent bacterial and opportunistic infections; it is also associated with normal to elevated serum IgM levels and a concomitant deficiency of IgG, IgA, and IgE. In this report, we give account of a boy with X‐linked HIGM and a novel Y172C mutation within his CD40LG gene. He presented with severe neutropenia as the dominating symptom. His bone marrow showed maturation arrest at the promyelocyte/myelocyte stage, typical of congenital neutropenia. This boy suffered from life‐threatening infections and required high doses of rhG‐CSF, and a haploidentical PBSCT was also successfully performed, thus leading to reconstitution of CD40L expression on activated CD4+ T cells (as assessed with flow cytometry six months after the procedure). Two low‐dose T‐cell addbacks were required to re‐establish full donor chimerism and clear CMV reactivation. The report demonstrates that in select cases, alternative donor allogeneic HSCT supported by DLI may be effective in correcting the defect in X‐linked HIGM, and HSCT in HIGM children is not necessarily limited to matched sibling donor transplantation.     

Allogeneic bone marrow transplantation for infantile globoid-cell leukodystrophy (Krabbe's disease)

A 4-month-old-girl affected by early expression of Krabbe's disease was treated with allogeneic bone marrow transplantation (BMT). The stem cell donor was her heterozygous HLA-identical mother. The central nervous system (CNS) involvement at diagnosis was evident, but minimal. After BMT the child presented a severe hypotonia and an acute tetraventricular hydrocephalus; she died 180 days after the BMT with progressive severe neurologic deterioration. Leukocyte galactocerebrosidase (GALC) activity was present at donor levels 20 days after BMT. Full donor chimerism was evident 18 days after BMT. This report confirms that in early onset "Krabbe's syndrome" if the diagnosis is delayed after the birth, the progression of the neurologic deterioration is not reversed by BMT. It is to be demonstrated if a very early hemopoietic stem cell transplantation during the first weeks of life, could be appropriate and efficacious.