Common ALL-associated antigen on cells and in the serum of common ALL patients: clinical relevance and biochemical characterization (author's transl)]

The clinical application of an antiserum recognizing common ALL associated antigen (cALL-AG) is very useful in classifying leukemias and diagnosing bone marrow relapse as well as CNS-leukemia. We could demonstrate that sera of common ALL (cALL) patients contain cALL-AG; its partial biochemical characterization is described. The anti cALL serum (cALL-AS) was raised in rabbits with cALL-cells precoated with rabbit antiserum against normal human lymphocytes. After appropriate absorbtion the cALL-AS was highly specific for cALL cells. The isolation of serum cALL-AG was performed by ammoniumsulfat precipitation, gel chromatography and affinity chromatography on agarose lens culinaris hemagglutinin A (lentil lectin). The apparent molecular-weight of the serum glycoprotein is 125 000. Two cALL-AG active structures could be solubilized from cALL cell membrane. The apparent molecular-weights were calculated to be 55 000 and 110 000.     

A role for metabolism in determining neonatal immune function

Immune responses of neonates differ markedly to those of adults, with skewed cytokine phenotypes, reduced inflammatory properties and drastically diminished memory function. Recent research efforts have started to unravel the role of cellular metabolism in determining immune cell fate and function. For studies in humans, much of the work on metabolic mechanisms underpinning innate and adaptive immune responses by different haematopoietic cell types is in adults. Studies investigating the contribution of metabolic adaptation in the unique setting of early life are just emerging, and much more work is needed to elucidate the contribution of metabolism to neonatal immune responses. Here, we discuss our current understanding of neonatal immune responses, examine some of the latest developments in neonatal immunometabolism and consider the possible role of altered metabolism to the distinctive immune phenotype of the neonate. Understanding the role of metabolism in regulating immune function at this critical stage in life has direct benefit for the child by affording opportunities to maximize immediate and long-term health. Additionally, gaining insight into the diversity of human immune function and naturally evolved immunometabolic strategies that modulate immune function could be harnessed for a wide range of opportunities including new therapeutic approaches.     

Recent aspects on the use of specific antisera in diagnosis and therapy of acute lymphatic leukaemia in infants (author's transl)]

Acute lymphatic leukaemia (ALL) in infants is a very heterogeneous disease from the immunological point of view. Phaenotyping of leukaemic cells in 138 patients via different immunmarkers has so far allowed subdivision into 6 subgroups. Clinical risk factors and correlations with the immunologically defined subgroups, as well as their significance for prognosis, are demonstrated with the help of 61 examined ALL patients. 90-95% of all acute lymphatic leukaemias can presently be identified via heterologous antisera. After corresponding absorption, these antisera show high cytotoxicity against ALL cells without displaying any aggressivity towards normal haemopoetic stem cells. The authors make therapeutic use of anti-T cell and anti-common ALL (cALL) globulin in autologous bone marrow transplantation. This method involves withdrawal of bone marrow from patients with ALL in complete remission, the marrow being then fractionated, treated with antiserum to destroy residual leukaemic cells, and then cryopreserved. The leukaemia-free bone marrow will thus be available for transplantation in relapse.     

Insights into the mechanisms of alveolarization - Implications for lung regeneration and cell therapies

Although the lung has extensive regenerative capacity, some diseases affecting the distal lung result in irreversible loss of pulmonary alveoli. Hitherto, treatments are supportive and do not specifically target tissue repair. Regenerative medicine offers prospects to promote lung repair and regeneration. The neonatal lung may be particularly receptive, because of its growth potential, compared to the adult lung. Based on our current understanding of neonatal lung injury, the ideal therapeutic approach includes mitigation of inflammation and fibrosis, and induction of regenerative signals. Cell-based therapies have shown potential to prevent and reverse impaired lung development. Their mechanisms of action suggest effects on both, mitigating the pathophysiological processes and promoting lung growth. Here, we review our current understanding of normal and impaired alveolarization, provide some rationale for the use of cell-based therapies and summarize current evidence for the therapeutic potential of cell-based therapies for pulmonary regeneration in preterm infants.     

Abnormal immune function in vivo in a murine model of lysosomal storage disease

Lysosomal storage diseases are a class of inborn errors of metabolism that lead to widespread disease in multiple tissues. The murine model of mucopolysaccharidosis type VII (MPS VII) closely parallels the human syndrome and has been extensively used to investigate the natural history and therapeutic strategies for lysosomal storage diseases in general. Here we demonstrate a previously undescribed immune defect in the MPS VII mouse. Although the normal populations of cells are present in lymph nodes of these mice, MPS VII mice show a blunted T cell proliferative response and decreased antibody production after immunization with antigens. One mechanism of this defect is ineffective processing of protein antigens, as responses to peptide antigens are normal. This phenotype is presumably caused by the lysosomal disorder, as the defect can be corrected in vivo by direct enzyme replacement therapy. These findings have implications for the use of this animal model, and may have clinical significance for other, more-common lysosomal storage diseases.     

嵌合抗原受体-T细胞治疗儿童肿瘤的临床研究进展

儿童肿瘤患者的5年生存率已达80%以上,但仍有部分复发难治性肿瘤通过传统治疗手段难以取得理想疗效。嵌合抗原受体(CAR)-T细胞技术的发展为治愈这些肿瘤带来了希望。CAR-T细胞通过非MHC限制性的方式识别肿瘤相关抗原,抗肿瘤能力显著增强,目前已发展到第四代。靶向CD19的CAR-T细胞治疗复发难治性急性淋巴细胞白血病缓解率高达90%,且可以通过桥接造血干细胞移植、供者CAR-T细胞输注等手段辅助白血病的治疗。实体瘤方面,靶向GD2的CAR-T细胞治疗神经母细胞瘤具有良好的反应性,但对其他实体瘤效果欠佳。CAR-T细胞治疗可能出现细胞因子释放综合征、脱靶效应、肿瘤溶解综合征、插入突变等毒副反应。靶向CD19的CAR-T细胞治疗虽有很高的缓解率,但复发率较高,包括CD19~+和CD19~-复发,其机制尚需进一步研究。     

Control of breathing and neonatal apnea

Great strides have been made in our understanding of developmental respiratory neurobiology. A clear picture is, therefore, emerging of the physiological mechanisms that underlie apnea of prematurity. The ventral surface of the medulla and adjacent areas play a key integrative function for central CO2 chemosensitivity and modulation of afferent inputs from peripheral chemoreceptors and laryngeal afferents. Maturational change in medullary neurotransmitter function appears to contribute to the physiological events that characterize apnea of prematurity. Despite this greater scientific insight, therapeutic strategies for neonatal apnea have changed little in 30 years. Xanthine therapy and continuous positive airway pressure remain the mainstay of therapy while other therapeutic approaches have been inadequately studied. Our understanding of a possible relationship between the triad of apnea, bradycardia and desaturation, and impaired neurodevelopmental outcome is also limited. These are all issues that need our attention if optimal therapy and outcome are to be provided for preterm infants with immature respiratory control.     

Defining leukemia stem cells in MLL-translocated leukemias: implications for novel therapeutic strategies

Hematological malignancies and probably many other tumors are dependent on highly proliferating and self-renewing cancer stem cells. An important question in the development of novel, less toxic antileukemic strategies specifically targeting leukemia stem cells is how closely leukemia stem cells are related to normal hematopoietic stem cells. It has been recently demonstrated that leukemia stem cells can be derived from different stages in normal hematopoiesis and have unique phenotypic and genetic features. Introduction of Mixed-lineage leukemia ( MLL)-fusion oncoproteins, frequently found in infant leukemias and therapy-related leukemias, into differentiated hematopoietic progenitor cells results in the generation of leukemias with a high frequency of leukemia stem cells. The progenitor-derived leukemia stem cells ectopically express a limited stem cell program while maintaining the global identity of differentiated myeloid cells. Development of therapeutic strategies that specifically target the leukemia stem cell program while sparing normal hematopoietic stem cells may represent a novel therapeutic approach in human leukemias with high efficacy yet less side effects.     

Pädiatrische Onkologie Molekulare Onkologie im Kindesalter

The molecular analyses of malignant diseases in childhood have contributed essentially to the identification of novel genes and have fundamentally increased our understanding of the mechanisms underlying tumorgenesis. These findings have contributed to the development of both diagnostic and prognostic markers useful in patient management. Furthermore, characteristic genetic alterations in malignant cells and functional consequences are increasingly being resolved allowing a more precise prediction of outcome of each patient and enhancing the development of disease-specific treatment strategies. Novel genetic techniques such as molecular profiling will lead to new drug development enabling targeted therapeutic intervention of disrupted biologic processes in tumor cells.     

Hereditary angioedema

PURPOSE OF REVIEW: Major advances have been made in understanding the clinical signs and symptoms, the pathophysiology and the treatment of hereditary angioedema. This disease that often begins in childhood is caused by partial absence of the plasma protein C1-inhibitor. At the present time five pharmaceutical companies are planning or conducting clinical trials of a variety of agents to treat acute attacks of this illness. Here we review our current understanding of this illness and the current approaches to treatment. RECENT FINDINGS: This disease is often missed in childhood or confused with other illness. The clinical signs and symptoms are reviewed. The importance of the kinin generating pathway and bradykinin in causing edema has become central to our understanding of pathophysiology. The many new approaches to therapy all appear promising. SUMMARY: Currently we have effective chronic therapy for this disease, although available drugs have real or potential difficulties in use in children. In the future it is likely that effective therapy for acute attacks of disease will become available in the US. It is important to recognize the clinical manifestations of this potentially fatal illness and to understand the therapeutic options.     

Anti-IgE therapy in allergic disease

PURPOSE OF REVIEW: Recombinant monoclonal humanized anti-IgE has put forward a fundamentally new concept for the control of allergic disorders. This review will present recent data from clinical studies with anti-IgE in asthma, allergic rhinitis, and food allergy and will examine the place of anti-IgE among current therapeutic options for the treatment of asthma. RECENT FINDINGS: Therapy with anti-IgE depresses circulating free IgE to the limits of detection, inhibits early- and late-phase responses to allergens, suppresses inflammation and improves the control of allergic diseases. In moderate to severe asthma it results in fewer exacerbations and a lower requirement for both corticosteroids and beta-agonists. IgE appears to be an important regulator of high-affinity Fc receptors (FcepsilonRI) and, in the mouse, to enhance mast cell survival and activation. IgE receptors have been found on diverse inflammatory cells. Anti-IgE reduces the expression of FcepsilonRI on inflammatory cells. Current work has documented a marked decrease in tissue eosinophils, lymphocytes, and interleukin-4-positive cells by anti-IgE treatment and has provided insight into the mechanisms underlying improved control of asthma. SUMMARY: Clinical studies with anti-IgE have promoted and will continue to advance the understanding of IgE-mediated disease mechanisms. They have documented its efficacy in the treatment of allergic diseases, but much remains to be learned about the most effective clinical strategies and the selection of patients for therapy.     

Cancer immunotherapy: will expanding knowledge lead to success in pediatric oncology?

The past 25 years have seen an increase in our understanding of immunology and further expansion in the clinical use of immunotherapeutic modalities. How immunotherapy will be integrated with chemotherapy, radiation, and surgery remains to be established. Although there have been successes in the field of immunotherapy, they have been inconsistent, and it is hoped that increased understanding of the basic principles of immunology will improve the consistency of beneficial effects. In this article, we briefly provide a general overview of our current understanding of the immune system, with a focus on concepts in tumor immunology, followed by a discussion of how these concepts are being used in the clinic.     

Current treatment and prognosis of Wilms’ tumor

Summary Thanks to the nationally and internationally organized efforts refinements in the therapy of Wilms’ tumor have allowed restructuring and reduction of therapeutic strategies. A decrease in tumor relapse and long term sequelae are the immediate goals which will no doubt be the result of tailoring chemotherapy and radiation therapy exposure together with improved surgical techniques and outstanding supportive care.     

Immuntherapeutische Behandlung therapierefraktärer und rezidivierter akuter lymphatischer Leukämien im Kindes- und Jugendalter

Acute lymphoblastic leukemia (ALL) represents the most frequent malignant disease in childhood and adolescence and offers a good prognosis with approximately 80% survival in first remission after polychemotherapy and radiotherapy. In addition,many children with relapsed or refractory ALL will still be cured by allogeneic hematopoietic stem cell transplantation (alloHSCT).However, therapeutic options are limited with a very poor prognosis in case of another relapse after alloHSCT.Here,immunotherapy strategies offer a promising alternative to another chemotherapy or second alloHSCT, which are mainly palliative and accompanied by high morbidity and mortality. Immunotherapy strategies aim at an improvement of the graft-versus-leukemia (GvL) effect.The therapeutic GvL effect is usually associated with graft-versus-host disease (GvHD).The definition of patients subgroups with an increased risk for relapse after alloHSCT gains growing importance for immunotherapy strategies.Promising approaches for separation of GvL-effect and GvHD after donor lymphocyte infusions, e.g. T-cell suicide gene therapy, will be described. Finally, vaccination strategies for ALL exist.     

Is your metabolism determined by (cell) fate?

The rise in the incidence of metabolic disease to become a major public health problem has been met with a substantial increase in research into both the clinical and basic science of metabolism. This work has revealed that the origins of metabolic diseases of adults can begin early in life. Furthermore, the age of onset of symptoms has been rapidly decreasing. Therefore, pediatricians should be critically involved in both the generation of new therapies as well as the institution of measures of disease prevention. This perspective examines how recent advances have improved our understanding of the development of metabolic diseases. A connection between glucocorticoids and the origins of metabolic disease is one enticing clue because of the clinical similarity between patients with glucocorticoid excess and those with metabolic disease. A unifying link was found by investigating the role of glucocorticoids on cell fate and differentiation of mesenchymal stem cells. We conclude that understanding the mechanisms by which glucocorticoids can modify how cell fate decisions are made holds promise for developing new therapies and preventative measures.     

Gene therapy for mucopolysaccharidoses: in vivo and ex vivo approaches

Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders caused by a deficiency in lysosomal enzymes catalyzing the stepwise degradation of glycosaminoglycans (GAGs). The current therapeutic strategies of enzyme replacement therapy and allogeneic hematopoietic stem cell transplantation have been reported to reduce patient morbidity and to improve their quality of life, but they are associated with persistence of residual disease burden, in particular at the neurocognitive and musculoskeletal levels. This indicates the need for more efficacious treatments capable of effective and rapid enzyme delivery to the affected organs, especially the brain and the skeleton. Gene therapy (GT) strategies aimed at correcting the genetic defect in patient cells could represent a significant improvement for the treatment of MPS when compared with conventional approaches. While in-vivo GT strategies foresee the administration of viral vector particles directly to patients with the aim of providing normal complementary DNA to the affected cells, ex-vivo GT approaches are based on the ex-vivo transduction of patient cells that are subsequently infused back. This review provides insights into the state-of-art accomplishments made with in vivo and ex vivo GT-based approaches in MPS and provide a vision for the future in the medical community.     

Future horizons in the treatment of enteric neuropathies

Enteric neuropathies comprise a vast and disparate array of congenital and acquired disorders of the enteric nervous system (ENS), reflecting both the complexity of its neuronal composition and the many interactions that modulate its function. Although present therapeutic strategies, largely limited to surgery and the provision of artificial nutrition, have transformed the early survival and life of sufferers, levels of morbidity and mortality remain unacceptably high. This highlights the need to develop new treatments for enteric neuropathies. In the last decade, the tremendous advances in molecular biology and genetics have significantly enhanced our understanding of ENS development and function. Coupled with equivalent progress in the fields of pharmacology and stem-cell biology, this has led to the identification of novel tools and targets for therapy, which either aim to optimise the function of the intrinsic ENS or replace/replenish components of an inadequate or dysfunctional ENS. This article reviews current work on a number of these interventions with a particular focus on the use of ENS stem cells as potential therapeutic tools for enteric neuropathies.     

Type 1 diabetes: New horizons in prediction and prevention

Significant advances have been made in our understanding of the pathogenesis of type 1 diabetes and our ability to predict risk for the condition. This knowledge is being used to develop new and innovative strategies to prevent type 1 diabetes or to prevent further destruction of beta cells in those who are newly diagnosed. Several multicentre studies are underway investigating the natural history of the disease, the genetics behind the disease and ways to stop the autoimmune reaction against beta cells (Type 1 Diabetes TrialNet, Type 1 Diabetes Genetics Consortium and the Trial to Reduce Diabetes in the Genetically at Risk [TRIGR] Study Group). The stage is set to find an agent or strategy to prevent type 1 diabetes or to preserve the residual beta cell mass in new-onset patients.     

Toll-like receptor signaling in sepsis

Despite extensive research, bacterial sepsis and its associated systemic inflammation remain a major cause of morbidity and mortality in the pediatric intensive care unit. Advances in molecular biology, however, have improved our understanding of this disease process and have opened up new avenues of potential therapeutic approaches. One such exciting area has been the substantial and still growing evidence that the mammalian immune system uses a family of Toll-like receptors (TLRs) to generate a response to molecular patterns present on invading microorganisms. In particular, TLR4 is part of a recognition complex for bacterial lipopolysaccharide (LPS), thus raising the likelihood of its involvement in the inflammatory response to bacterial sepsis. This review highlights our understanding of the molecular biology of these receptors, focusing on the LPS response, and concluding with a summary of ongoing evaluation and potential therapeutic strategies for treating sepsis through blockade of TLR signaling.