Upregulation of α‐enolase in acute rejection of cardiac transplant in rat model: Implications for the secretion of interleukin‐17

Acute allograft rejection remains a major problem in solid organ transplantation. The enzyme α‐enolase has been shown to induce an immune response in cardiac transplantation. In this study, we investigated the role of α‐enolase in acute allograft rejection in a rat model of heart transplantation. Hearts from either (WF: RT1^u) or (Lew: RT1¹) rats were transplanted into (Lew: RT1¹) rats. No rejection occurred in the isograft group, for which the median survival time was >168 days, whereas the median survival time of the allograft group was significantly less at 10 ± 2.1 days (n = 8 per group, p < 0.001). Increased inflammation was observed in allografts, including increased α‐enolase expression and increased numbers of infiltrating CD4⁺ T cells (p < 0.05). By immunohistochemical staining, we confirmed that α‐enolase was expressed not only in myocardial cells but also in the infiltrating lymphocytes. However, on the fifth day after transplantation, α‐enolase expression was no longer observed in the lymphocytes (n = 3, p < 0.001). In contrast, no lymphocytes were found in isografts after transplantation (n = 3, p < 0.001). α‐enolase expression was increased in lymphocytes, which are implicated in the acute rejection of cardiac transplants. Intragraft α‐enolase inhibition may be useful as an adjuvant therapy to systemic immunosuppression in heart transplantation.     

Clinical and hematological features of homozygous hemoglobin O‐Arab [beta 121 Glu → Lys]

Hemoglobin O‐Arab [Beta 121 Glu → Lys] (Hb O‐Arab) is a rare abnormal hemoglobin (Hb) whose clinical and hematological features have been described in adults but not in children. We report three children, 9, 12, and 36 months of age, with homozygous Hb O‐Arab and assess the value of supplementary folic acid as treatment. Pediatr Blood Cancer 2013; 60: 506–507. © 2012 Wiley Periodicals, Inc.     

Myeloid lineage switch following chimeric antigen receptor T‐cell therapy in a patient with TCF3‐ZNF384 fusion‐positive B‐lymphoblastic leukemia

A pediatric patient diagnosed initially with B‐lymphoblastic leukemia (B‐ALL) relapsed with lineage switch to acute myeloid leukemia (AML) after chimeric antigen receptor T‐cell (CAR‐T) therapy and hematopoietic stem cell transplant. A TCF3‐ZNF384 fusion was identified at diagnosis, persisted through B‐ALL relapse, and was also present in the AML relapse cell population. ZNF384‐rearrangements define a molecular subtype of B‐ALL characterized by a pro‐B‐cell immunophenotype; furthermore, ZNF384‐rearrangements are prevalent in mixed‐phenotype acute leukemias. Lineage switch following CAR‐T therapy has been described in patients with KMT2A (mixed lineage leukemia) rearrangements, but not previously in any patient with ZNF384 fusion.     

Evidence for BCR/ABL1‐positive T‐cell acute lymphoblastic leukemia arising in an early lymphoid progenitor cell

BCR‐ABL1‐positive leukemias have historically been classified as either chronic myelogenous leukemia or Ph+ acute lymphoblastic leukemia. Recent analyses suggest there may be a wider range of subtypes. We report a patient with BCR‐ABL1 fusion positive T‐cell ALL with a previously undescribed cell distribution of the fusion gene. The examination of sorted cells by fluorescence in situ hybridization showed the BCR‐ABL1 fusion in the malignant T cells and a subpopulation of the nonmalignant B cells, but not nonmalignant T cells or myeloid or CD34+ progenitor cells providing evidence that the fusion may have occurred in an early lymphoid progenitor.     

Munc13‐4 deficiency with CD5 downregulation on activated CD8+ T cells

Familial hemophagocytic lymphohistiocytosis (FHL) is characterized by uncontrolled activation of T cells and macrophages and hypercytokinemia. We have recently described a significant increase in a subpopulation of CD8⁺ T cells with downregulation of CD5 during the acute phase of FHL type2 (FHL2; perforin deficiency), which declines after successful treatment, with a concomitant reduction in serum cytokine level. This unusual subset of CD8⁺ T cells, however, has not been characterized in patients with other subtypes of FHL. Herein, we describe a patient with FHL3 (Munc13‐4 deficiency) carrying compound heterozygous mutations in the UNC13D gene. He had high serum levels of pro‐inflammatory cytokines and significantly increased activated CD8⁺ T cells with downregulation of CD5 during the acute phase, similar to that found in FHL2. This immunophenotypic feature may serve as a useful marker of immune dysregulation in FHL3 in addition to FHL2.     

CD56‐negative extranodal nasal type NK/T‐cell lymphoma

Extranodal natural killer (NK)/T‐cell lymphoma, nasal type, is a rare lymphoma that occurs predominantly in Asian adults. In this report, we describe the clinical and pathologic features of an unusual aggressive lymphoid neoplasm in a child and review the literature on NK/T‐cell lymphoma in children. The patient was a 4‐year‐old Native American male with facial swelling, lymphadenopathy, and fevers. Biopsy demonstrated neoplastic lymphoid cells that expressed CD3, CD8, TIA‐1, and EBV‐encoded RNA without CD56. The patient failed multiagent chemotherapy and died of therapy‐related complications. This case represents an extranodal NK/T‐cell lymphoma, nasal type, with an unusual lack of CD56. Pediatr Blood Cancer 2010;55:186–189. © 2010 Wiley‐Liss, Inc.     

The response of bovine beta‐lactoglobulin‐specific T‐cell clones to single amino acid substitution of T‐cell core epitope

Cow’s milk is one of the most common food allergens in the first year of life, with approximately 2.5% of infants experiencing an allergic reaction to it. Beta‐lactoglobulin (BLG) is one of the major allergens in cow’s milk. Previously, we reported that four of six T‐cell clones (TCC) which were established from cow’s milk allergy patients recognized BLGp97‐117 as the core sequence and also recognized BLG in association with the human leucocyte antigen (HLA)‐DRB1*0405 allele. Using two of these four TCCs, we evaluated the T‐cell response to BLG peptides with single amino acid substitution or deletion and identified BLGp102‐112 as the minimum essential region in BLGp97‐117. In the alanine‐scan assay, the proliferative responses of TCCs to pE108A disappeared, and the proliferative responses of TCCs to pC106A decreased. In the analog peptide proliferation assay, pY102S had retained some T‐cell response to the two TCCs. Collecting these results, we propose a motif for the interaction between the HLA‐DRB1*0405 allele and antigen peptide, and suggest that BLGp105‐108 are important residues to retain the TCR/BLG‐peptide/HLA complex. pY102A and pY102S are partial agonists for the T‐cell receptor. These peptides might be considered as candidate peptides for the modification of the T‐cell response to BLG in cow’s milk allergy.     

Successful treatment of post‐transplant CMV meningoencephalitis with third‐party CMV virus‐specific T cells: Lessons learned

Cytomegalovirus encephalitis is a challenging life‐threatening complication following hematopoietic stem cell transplantation for which medical treatment is usually ineffective or toxic. However, in recent years, adoptive T‐cell therapy has been reported to provide a significant chance of cure for patients with viral infections. Herein, two cases of pediatric patients successfully treated with third‐party donor‐derived virus‐specific T cells for CMV meningoencephalitis are reported.     

A 5‐HT2A/2C receptor agonist, 1‐(2,5‐dimethoxy‐4‐iodophenyl)‐2‐aminopropane,mitigates developmental neurotoxicity of ethanol to serotonergic neurons

Prenatal ethanol exposure causes the reduction of serotonergic (5‐HTergic) neurons in the midbrain raphe nuclei. In the present study, we examined whether an activation of signaling via 5‐HT_2A and 5‐HT_2C receptors during the fetal period is able to prevent the reduction of 5‐HTergic neurons induced by prenatal ethanol exposure. Pregnant Sprague–Dawley rats were given a liquid diet containing 2.5 to 5.0% (w/v) ethanol on gestational days (GDs) 10 to 20 (Et). As a pair‐fed control, other pregnant rats were fed the same liquid diet except that the ethanol was replaced by isocaloric sucrose (Pf). Each Et and Pf group was subdivided into two groups; one of the groups was treated with 1 mg/kg (i.p.) of 1‐(2,5‐dimethoxy‐4‐iodophenyl)‐2‐aminopropane (DOI), an agonist for 5‐HT_2A/2C receptors, during GDs 13 to 19 (Et‐DOI or Pf‐DOI), and another was injected with saline vehicle only (Et‐Sal or Pf‐Sal). Their fetuses were removed by cesarean section on GD 19 or 20, and fetal brains were collected. An immunohistological examination of 5‐HTergic neurons in the fetuses on embryonic day 20 using an antibody against tryptophan hydroxylase revealed that the number of 5‐HTergic neurons in the midbrain raphe nuclei was significantly reduced in the Et‐Sal fetuses compared to that of the Pf‐Sal and Pf‐DOI fetuses, whereas there were no significant differences between Et‐DOI and each Pf control. Thus, we concluded that the reduction of 5‐HTergic neurons that resulted in prenatal ethanol exposure could be alleviated by the enhancement of signaling via 5‐HT_2A/2C receptors during the fetal period.     

Relationship between cytotoxic T‐lymphocyte antigen 4 ‐318C/T (rs5742909) gene polymorphism and the risk of acute rejection in renal transplantation

Results on the relationship between CTLA4 ‐318C/T (rs5742909) gene polymorphism and risk of acute rejection in renal transplantation are still conflicting. This meta‐analysis was performed to update the association between CTLA4 ‐318C/T and risk of acute rejection in renal transplantation. The association investigations were identified from PubMed and Cochrane Library, and eligible studies were included and synthesized using meta‐analysis method. Twelve reports were included in this meta‐analysis for the association of CTLA4 ‐318C/T gene polymorphism with acute rejection risk in renal transplantation, consisting of 728 acute rejection patients and 1628 non‐acute rejection controls. The association between CTLA4 ‐318C/T gene polymorphism and acute rejection risk in renal transplantation for overall populations was not found in this meta‐analysis (T allele: OR=0.96, 95% CI: 0.60‐1.54, P=.88; TT genotype: OR=0.90, 95% CI: 0.47‐1.71, P=.74; CC genotype: OR=1.00, 95% CI: 0.62‐1.59, P=.98). Interestingly, T allele was associated with the risk of acute rejection in renal transplantation in African population. In conclusion, CTLA4 ‐318C/T gene polymorphism is not associated with the risk of acute rejection in renal transplantation in overall populations.