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Hematopoietic Stem Cell Transplantation for Primary Immunodeficiency Disease

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Bone Marrow Transplantation (2008) 41, 119–126 & 2008 Nature Publishing Group All rights reserved 0268-3369/08 $30.00 www.nature.com/bmt REVIEW Hematopoietic stem cell transplantation for primary immunodeficiency disease CC Dvorak and MJ Cowan Department of Pediatrics, Blood and Marrow Transplant Division, UCSF Children’s Hospital, San Francisco, CA, USA Hematopoietic stem cell transplantation is the definitive SCID therapy for a variety of rare primary cellular immuno- deficiency syndromes diagnosed in children. All primary SCID is a rare disease caused by a group of genetic immunodeficiencies benefit from early diagnosis and disorders with a shared phenotype of deficient T- and transplantation before the development of serious infec- B-lymphocyte function (with or without abnormal natural tions, which contribute to a significant increased risk of killer (NK) cell development) that leads to early death from mortality following transplant. In the absence of a recurrent infections in affected children (Table 2). In matched sibling, parental haplocompatible, matched un- addition, since SCID patients are unable to reject foreign related donor and cord blood stem cells have all been cells, a significant percentage of patients will have evidence utilized with varying degrees of success and immune of maternally engrafted T lymphocytes, which often leads reconstitution. The role of pretransplant conditioning in to clinical manifestations of GVHD.1 Exceptfor those patients with SCID disease in terms of its effects upon patients with SCID due to deficiency of adenosine T- and B-cell immune reconstitution and late effects is deaminase (ADA), for which a replacementenzyme exists, still under debate and will require further study. the only curative therapy for SCID is allogeneic HSCT. Bone Marrow Transplantation (2008) 41, 119–126; However, early results with gene insertion into autologous doi:10.1038/sj.bmt.1705890; published online 29 October 2007 hematopoietic stem cells for children with X-linked SCID Keywords: primary immunodeficiency; SCID; transplant- and ADA deficiency2 suggest that eventually, this will ation; HSCT become a more common form of curative treatment for many primary immunodeficiency diseases. At the time of diagnosis, patients with SCID generally have already developed, or are at an extremely elevated risk of developing, a life-threatening infection. This necessitates Introduction rapid initiation of HSCT. For all stem cell sources, successful outcomes are more likely to be achieved when Primary cellular immunodeficiencies are a group of the patient is still very young, preferably less than 6 months inherited disorders characterized by severe impairment of age.3,4 Buckley et al.,5 demonstrated that infants of the innate or adaptive immune systems, which transplanted less than 3.5 months of age had a 95% overall generally leads to early death from infectious complica- survival (OS), compared to only 76% OS in older children. tions. These disorders can be further categorized by the cell This is likely due to the development of pulmonary lineage(s) primarily affected (Table 1). While improved infections prior to transplant, which have been associated supportive care has extended the life span of patients with significantly poorer outcomes.4,6 In addition, trans- affected by these diseases, definitive cure is generally only plants performed within the first month of life are achieved by allogeneic hematopoietic stem cell transplanta- associated with more rapid T-cell reconstitution, perhaps tion (HSCT), though recent advances in gene therapy hold due to superior thymic capacity.7 significant promise that this may soon be a viable alternative. Impact of SCID phenotype T-B þ NKÀ SCID The mostcommon form of SCID, accountingfor approximately 50% of all cases, is due to a defect in the Correspondence: Dr MJ Cowan, Department of Pediatrics, Blood and gene for the common gamma chain (gc) located on Xq13. Marrow TransplantDivision, UCSF Children’s Hospital,505 Parnassus Another defect, JAK3 deficiency, results in a similar Avenue, San Francisco, CA 94143-1278, USA. E-mail: [email protected] T-B þ NKÀ phenotype (Table 2). Post transplant, patients Received 24 August 2007; revised 14 September 2007; accepted 14 with gc deficiency have been noted to have excellent rates of September 2007; published online 29 October 2007 sustained thymic output, as measured by levels of T-cell BMT for immunodeficiency diseases CC Dvorak and MJ Cowan 120 Table 1 Primary immunodeficiencies potentially treated with HSCT Absent T- and B- Defective T and B lymphocytes Dysfunctional T lymphocytes with Absent or dysfunctional granulocytes lymphocyte function predisposition to HLH SCID Wiskott–Aldrich syndrome Familial HLH (defects in perforin, Severe congenital neutropenia MUNC, etc.) HIGM1 Chediak–Higashi syndrome Leukocyte adhesion disorder Griscelli syndrome Chronic granulomatous disease XLP Abbreviations: HIGM1 ¼ hyper IgM syndrome (CD40 ligand deficiency); HLH ¼ hemophagocytic lymphohistiocytosis; XLP ¼ X-linked lymphoprolifera- tive disease. Table 2 Genetic subtypes of severe combined immunodeficiency Name Defect Phenotype Special X-linked Common g chain T-B+NKÀ JAK3 deficiency Janus kinase 3 T-B+NKÀ Rag 1 or 2 Recombinase-activating T-BÀNK+ Frequently associated with Omenn’s proteins 1 or 2 syndrome: autoreactive GVHD Artemis deficiency Artemis (also known as T-BÀNK+ Athabascan-speaking Native Americans, DCLRE1C) radiosensitive Ligase 4 deficiency Ligase 4 T-BÀNK+ Radiosensitive IL-7Ra deficiency IL-7 receptora T-B+NK+ CD45 deficiency CD45 T-B+NK+ CD3d deficiency CD3d subunitT-B+NK+ CD3e deficiency CD3e subunitT-B+NK+ CD3B deficiency CD3B subunitT-B+NK+ Cartilage hair hypoplasia Endoribonuclease T-B+NK+ Dwarfism, hypoplastic hair Finnish, Amish p56lck deficiency p56lck Protein tyrosine kinase T-B+NK+ ADA deficiency Adenosine deaminase T-BÀNKÀ PNP deficiency Purine nucleoside T-BÀNKÀ Neurologic dysfunction, ataxia phosphorylase Reticular dysgenesis Unknown T-BÀNKÀ Impaired myeloid and erythroid development, sensorineural deafness ZAP70 deficiency B-chain-associated protein kinase CD4+, CD8À B+, NK+ Bare lymphocyte Syndrome type II HLA class II CD4À(mild), CD8+ North African B+, NK+ SCID with bowel atresia Unknown CD4+, CD8+, B+NK+ Abbreviations: ADA ¼ adenosine deaminase; DCLREIC ¼ DNA cross-link repair enzyme 1C; HLA ¼ human leukocyte antigen. receptor excision circles (TRECs). This may be due to a has been attributed to a diminished rate of engraftment, pre-transplant low level of thymic precursors in these increased severity of GVHD, higher incidence of chronic patients, which post transplant allows for thymic seeding of GVHD4 and slower recovery of T-cell function.6,9 The very early progenitors.8 relatively poor engraftment in patients with T-BÀNK þ SCID is in large part due to the presence of host NK cells, which are capable of mediating donor stem cell rejection.4 T-BÀNK þ SCID Studies in animal models of NK þ SCID,10 as well as It has been estimated that 20–30% of all SCID cases have unpublished data in our own laboratory with an Artemis- the T-BÀNK þ phenotype with defects in RAG1 or RAG2 deficientmouse model, supporttherole of NK cells in graft being the most common etiology. It has been reported that resistance. B-phenotypes (presumably NK þ ) of SCID have signifi- cantly poorer 3-year OS (36%) compared with B þ phenotypes (64%).6 Bertrand et al.4 demonstrated a worse SCID due to DNA repair defects disease-free survival after T-depleted haplocompatible A subsetof T-B ÀNK þ SCID patients have increased transplant in patients with BÀ SCID (35%) compared cellular sensitivity to alkylating agents and ionizing with B þ SCID (60%). Haddad et al.9 has also shown a radiation, mainly due to a deficiency in the gene for worse long-term outcome in children with BÀ SCID (NK Artemis, a critical protein in the nonhomologous DNA cell phenotype unknown), who were more likely to die repair pathway.11 Unlike other forms of BÀ SCID, patients during the first 6 months post transplant (37%) compared with Artemis deficiency have undergone HSCT with with those who had B þ SCID (13%). This poor survival an excellentOS of 75%. 11 A new type of radiosensitive Bone Marrow Transplantation BMT for immunodeficiency diseases CC Dvorak and MJ Cowan 121 T-BÀNK þ SCID has been recently described with a defect cells from this source makes this option unfeasible for most in DNA ligase IV, an enzyme in the nonhomologous DNA cases of SCID, in which HSCT is urgently indicated. repair pathway distal to Artemis.12 Haplocompatible-related donors T-B þ NK þ SCID With the advent of effective T-cell depletion strategies, the Another subset of SCID patients is characterized by the use of haplocompatible family members as donors for presence of both B cells and NK cells. A variety of cellular children with SCID has become a viable strategy. Three- defects have been reported to result in this phenotype, year survivals of 53–79% have been reported, with including deficiencies of IL-7 receptor-a, CD45 and the significantly better success rates in more recent years and CD3d, CD3e and CD3B subunits. Most of these deficiencies in more experienced centers,3,5,6,14 especially if the trans- have only recently been discovered and very small numbers plantis performed early before thedevelopmentof life- of these patients have been followed long term after HSCT, threatening infections. In SCID patients with evidence of making definitive statements regarding their clinical course maternal engraftment,1 the mother is typically utilized as difficult. the stem cell source (unless an HLA-matched sibling is available), since the recipient is already tolerant to the maternal cells. A potential risk with this approach is the T þ SCID Rare forms of SCID are characterized by the selective development of GVHD by the maternally engrafted T cells following the infusion of maternal bone marrow cells. In absence of CD4 þ T cells (for example, HLA class II our own experience this has not been a significant problem deficiency) or CD8 þ T cells (for example, ZAP70 deficiency).
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    Ulm University Medical Center Institute for Transfusion Medicine Prof. Dr. med. Hubert Schrezenmeier Investigations on the Molecular Biology of Human Adenylate Kinase 2 Deficiency (Reticular Dysgenesis) and the Establishment and Characterisation of an Adenylate Kinase 2-deficient Mouse Model Dissertation to obtain the doctoral degree of Human Biology (Dr. biol. hum.) of the Medical Faculty of Ulm University Rebekka Waldmann Ulm 2017 Amtierender Dekan: Prof. Dr. rer. nat. Thomas Wirth 1. Berichterstatter: Prof. Dr. med. Hubert Schrezenmeier 2. Berichterstatter: PD Dr. med. Manfred Hönig Tag der Promotion: 13.04.2018 Index Index INDEX OF ABBREVIATIONS ........................................................................................................................... I 1 INTRODUCTION ..................................................................................................................................... 1 1.1 SEVERE COMBINED IMMUNODEFICIENCIES (SCIDS) ........................................................................................ 1 1.2 RETICULAR DYSGENESIS ............................................................................................................................. 2 1.3 ADENYLATE KINASES ................................................................................................................................. 3 1.4 IMMUNODEFICIENT MOUSE MODELS ........................................................................................................... 7 1.5 AIM OF THE STUDY ..................................................................................................................................