Congenital Disorders of Lymphocyte Function

Over 350 molecular defects that result in primary immune deficiency are known to date. Many of these gene defects have been identified in recent years with the advent of whole-exome and whole-genome sequencing. The study of patients with primary immune deficiencies has unraveled fundamental mechanisms that govern lymphocyte development and function. Importantly, characterization of the molecular basis of these diseases has revealed unanticipated heterogeneity of the clinical and immunological phenotype. This chapter reviews disorders of thymus organogenesis, severe combined immune deficiency (SCID), other combined immunodeficiencies, disorders with immune dysregulation, and defects of humoral immunity.

Defects of Thymus Organogenesis

The thymus is the primary organ where T lymphocytes are generated and educated. Endoderm-derived thymic stem cells derived from the third pharyngeal pouch differentiate into cortical and medullary epithelial cells, which in turn induce the differentiation of hematopoietic precursors into T cells. Thus, defects of thymus organogenesis have important consequences on immune function.

DiGeorge Syndrome

DiGeorge syndrome (DGS) is caused by developmental anomalies of the third and fourth pharyngeal pouches, and is characterized by thymic hypoplasia, hypoparathyroidism, conotruncal heart malformations, which are a group of congenital cardiac outflow tract anomalies that include such defects as tetralogy of Fallot, pulmonary atresia with ventricular septal defect, double-outlet right ventricle, double-outlet left ventricle, truncus arteriosus and transposition of the great arteries, interrupted aortic arch type B among others, and facial dysmorphisms (micrognathia, hypertelorism, antimongoloid slant of the eyes, cleft palate, and ear malformations). Hypocalcemic seizures are common. Feeding problems, microcephaly, speech delay, neurobehavioral problems (including bipolar disorders, autistic spectrum disorders, and schizophrenia later in life), and scoliosis are frequently observed.

Between 50% and 90% of patients with DGS carry a hemizygous deletion of chromosome 22q11, which occurs in ~1:3000 newborns, most arising de novo. Fluorescent in situ hybridization (FISH) and multiplex ligation-dependent probe amplification (MLPA) readily identify the 22q11del in most cases. More rarely, DGS is associated with mutations of the TBX1 gene, contained within the 22q11 interval, or with 10p deletion.

Most patients have “partial DGS,” manifested by mild T-cell lymphopenia and immunodeficiency. Such patients may be asymptomatic, may have oral thrush and recurrent infections, or may develop autoimmune disease such as juvenile idiopathic arthritis, immune thrombocytopenic purpura, and Raynaud phenomenon. Approximately 1% of DGS patients have “complete DGS,” with absence of circulating T cells. Some DGS patients may develop low numbers of oligoclonal T lymphocytes that undergo activation in vivo and infiltrate target tissues, causing skin rash, liver dysfunction, and lymphadenopathy. This condition is known as complete atypical DGS.

Treatment of DGS includes correction of severe heart defects, and supplementation with calcium and vitamin D to correct the hypocalcemia. If a significant immune defect is present, prophylaxis of Pneumocystis jiroveci pneumonia with trimethoprim-sulfamethoxazole (TMP-SMZ) is indicated. Live-attenuated vaccines can be safely administered to patients with partial DGS who have good cellular immunity (with CD8 ⁺ count >300 cells/μL); however, these vaccines are contraindicated in patients with complete DGS. Use of immunosuppressive drugs is indicated in patients with complete atypical form of the disease.

Ultimately, survival in patients with complete DGS requires immune reconstitution. Stem cell transplantation from human leukocyte antigen (HLA)-identical donors may allow engraftment of mature T cells contained in the graft. However, because of the absence of thymic tissue, newly developed T cells are not generated, and the patient may remain susceptible to pathogens that are not recognized by donor-derived T cells contained in the graft.

By contrast, thymic transplantation represents the treatment of choice for patients with complete DGS, including the atypical variant. The thymus obtained as discarded tissue from unrelated infants undergoing heart surgery is sliced and cultured in vitro, then implanted in the quadriceps muscles of the infant. In most cases, naïve T cells appear at around 4 to 7 months of age; these cells are tolerant to donor thymic cells, display a polyclonal repertoire, and have normal proliferative capacity. Although the number of CD3+ T cells in transplanted patients often remains lower than normal, their diversity and function are sufficient to prevent life-threatening infections. The success of this treatment has recently led to approval of this therapy by the Food and Drug Administration in the United States.

FOXN1 Deficiency

The transcription factor FOXN1 (whose gene is mutated in the nude mouse) plays a critical role in thymus and eccrine glands development. FOXN1 mutations in humans cause athymia, profound T-cell lymphopenia, alopecia totalis, and nail dystrophy. Similar to DGS, reconstitution of T-cell immunity can be achieved with thymic transplantation. FOXN1 haploinsufficiency may also cause T-cell lymphopenia at birth, followed by gradual and partial recovery of T-cell count.

CHARGE Syndrome

This syndrome is characterized by the association of coloboma (a hole in one of the structures of the eye, such as the iris, retina, choroid, or optic disc), heart anomalies, choanal atresia, mental retardation, genital and ear anomalies, and immunodeficiency. Most cases are sporadic and represent de novo mutations of the CHD7 or of the SEMA3E genes. The immunodeficiency is secondary to defects of thymic development. There is a variable degree of T-cell lymphopenia, which in some cases is very severe, resembling SCID.

PAX1 Deficiency

Paired Box 1 (PAX1) is a transcription factor involved in early stages of pharyngeal pouch differentiation and thymus development. Autosomal recessive PAX1 deficiency is characterized by T-cell lymphopenia associated with facial anomalies, hearing loss, vertebral anomalies and neurodevelopmental problems.

Severe Combined Immune Deficiency Due to Early Defects in T-Lymphocyte Development

SCID, the most severe form of congenital immunodeficiency, is caused by defects that completely abrogate the development of T lymphocytes, and in some cases also B and/or natural killer (NK) lymphocytes. Advances in the genes responsible, newborn screening, and gene therapy have had a strong impact on the diagnosis and therapy of SCID.

Pathobiology and Genetics

Genetic defects that cause SCID affect various stages in T-cell development ( Fig. 52.1 ), and can be grouped into three major categories: (1) defects in cytokine receptor signaling; (2) defects in lymphocyte survival; and (3) defects of expression and function of the pre–T-cell receptor

Figure 52.1, GENETIC DEFECTS ASSOCIATED WITH SEVERE COMBINED IMMUNE DEFICIENCY (SCID).

Cytokine Receptor Signaling Defects

The most common form of SCID in humans is the X-linked form due to mutations of the IL2RG gene, which encodes for the common gamma chain (γc). This protein is shared by receptors for interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21, and signals through the intracellular kinase Janus-activated kinase (JAK)3. Patients with mutations in IL2RG or JAK3 lack both T and NK cells, since development of these subsets depends on IL-7- and IL-15-mediated signaling, respectively. B lymphocytes are present but antibody production is impaired because of the lack of T cells and defective signaling through the IL-21R.

Defects in Lymphocyte Survival

Proliferation and survival of lymphoid progenitor cells are essential to permit generation of a normal number of mature lymphocytes. Some forms of SCID are associated with increased apoptosis. Adenosine deaminase (ADA) converts adenosine to inosine (and deoxyadenosine to deoxyinosine). In patients with ADA deficiency, accumulation of toxic phosphorylated derivatives of deoxyadenosine causes cell death and results in extreme lymphopenia, with virtual absence of T, B, and NK lymphocytes. Reticular dysgenesis (RD) is a form of SCID characterized by the association of severe lymphopenia, agranulocytosis, and sensorineural deafness (see Chapter 30 ). RD is caused by defects in adenylate kinase 2 (AK2), resulting in increased sensitivity to reactive oxygen species and increased apoptosis.

Defects of Expression and Signaling Through the Pre–T-Cell Receptor and the T-Cell Receptor

Rearrangement of the T-cell receptor (TCR) genes by means of variable diversity joining (V(D)J) recombination allows expression of the pre-TCR (composed of the pre-Tα and the TCRβ chain), and of mature forms (TCRαβ and TCRγδ) of the TCR.

The lymphoid-specific recombinase-activating genes (RAG1 and RAG2) proteins initiate V(D)J recombination by recognizing recombination-specific sequences that flank the V(D)J elements of the TCR and of immunoglobulin genes, introducing DNA double-strand breaks. These are then repaired through the ubiquitously expressed nonhomologous end-joining (NHEJ) pathway. Mutations of the RAG1 and RAG2 genes, and genes that encode for Artemis, DNA ligase IV, and DNA-protein kinase catalytic subunit (all components of the NHEJ pathway), result in SCID with a lack of T and B lymphocytes (see Figs. 52.1 and 52.2 ), but normal numbers of NK lymphocytes. Mutations of the NHEJ1 gene (encoding Cernunnos/XLF, another component of the NHEJ pathway) severely impair, but do not completely abrogate, T- and B-cell development. Because NHEJ is involved in general mechanisms of DNA repair involving nonlymphoid cells, patients with defects of this pathway also show increased radiation sensitivity, are at a higher risk of tumors. In addition, neurologic problems are common, except in patients with Artemis deficiency.

Figure 52.2, GENETIC DEFECTS ASSOCIATED WITH HYPOGAMMAGLOBULINEMIA.

Signaling through the pre-TCR/CD3 complex is essential to promote progression from CD4-CD8- double-negative (DN) to CD4 ⁺ CD8 ⁺ double-positive (DP) stage of thymocyte development. Mutations of the CD3δ ( CD3D ), CD3ε ( CD3E ), and CD3ζ ( CD3Z ) chains interfere with this process and result in SCID. In contrast, mutations of CD3γ ( CD3G ) are more often associated with a milder phenotype that includes autoimmunity. Downstream of the TCR/CD3 complex, mutations of the Linker for Activation of T cells (LAT), also perturb signaling and cause T ⁻ B ⁺ SCID. Finally, mutations of the CD45 phosphatase, also involved in cell signaling, cause T ⁻ B ⁺ SCID.

Clinical and Laboratory Manifestations

Typical clinical features of SCID include early-onset severe infections caused by bacteria, viruses, fungi, and opportunistic pathogens (including P. jiroveci pneumonia), protracted diarrhea, candidiasis, and failure to thrive. Engraftment of maternally derived T lymphocytes is common in SCID. The patient may be asymptomatic or may present with symptoms similar to graft-versus-host disease (GVHD): skin rash, elevation of liver enzymes, diarrhea, and cytopenias. Hypomorphic mutations in SCID-causing genes may lead to residual development of T cells that undergo peripheral expansion and infiltrate target organs, causing various symptoms (erythroderma, diarrhea, hepatosplenomegaly, lymphadenopathy, diarrhea). This clinical phenotype is also known as Omenn syndrome .

Some forms of SCID may present with additional clinical features (see earlier section on Defects in Thymic Development). In patients with ADA deficiency, accumulation of toxic metabolites may cause cupping and flaring of the ribs, liver dysfunction, sensorineural deafness and neurobehavioral problems. Microcephaly is often seen in forms of SCID associated with radiosensitivity and impairment of DNA double-strand break repair. Sensorineural deafness is observed in RD.

A family history (including consanguinity, deaths in infancy, and the gender of other affected family members) may be suggestive of X-linked versus autosomal recessive inheritance patterns. Measurement of absolute lymphocyte count (ALC) and the absolute number of CD3 ⁺ T cells, CD4 ⁺ and CD8 ⁺ T-cell subsets, CD19 ⁺ B cells, and NK cells (CD16 ⁺ /CD56 ⁺ NK lymphocytes) confirms the diagnosis and may direct the work-up towards specific gene defects. The presence of CD3 ⁺ cells in a child with clear clinical manifestations of SCID may indicate maternal T-cell engraftment or may be due to hypomorphic mutations that allow residual T-cell development. In both of these situations, the T cells have an activated/memory (CD45RO ⁺ ), whereas T cells in normal infants are predominantly naive (CD45RA ⁺ ). In vitro proliferative responses to mitogens are drastically reduced in patients with SCID, but may be partially preserved in infants with Omenn syndrome. A chest X-ray with a lack of a thymic shadow supports the diagnosis of SCID. Serum IgA and IgM levels are low to undetectable, but IgG levels may be normal early in life, reflecting the transplacental passage of maternally derived antibodies. (See box on Diagnostic Approach to Severe Combined Immune Deficiency.)

Diagnostic Approach to Severe Combined Immune Deficiency

SCID presents early in life with severe infections of bacterial, viral, or fungal origin.
Opportunistic infections are common in infants with SCID.
Respiratory infections, protracted diarrhea, and failure to thrive are typical signs at presentation.
Lymphopenia is present in 50%–70% of infants with SCID. Age-specific norms must be used in evaluating the ALC since infants and children have much higher ALCs than adults (3500–13,000 in very young infants versus 1000–2800 in adults).
T-cell lymphopenia is the hallmark of the disease; abnormalities of the absolute number of B and NK lymphocytes are observed in some forms of SCID. However, T lymphocytes may be present in SCID infants with maternal T-cell engraftment or with hypomorphic mutations in SCID-associated genes that allow residual T-cell development. Thus, a normal ALC does not rule out SCID.
Maternally engrafted T cells proliferate in the infant with SCID in vivo, but the vast majority do not proliferate in vitro when stimulated with traditionally used mitogens such as concanavalin A and phytohemagglutinin, as measured by thymidine incorporation. Thus, if SCID is suspected, but T cells are detectable, maternal engraftment studies and proliferation to mitogens must be evaluated.
Universal newborn screening for SCID, based on enumeration of TRECs by quantitative PCR, has been implemented in the United States and in several other countries worldwide. TRECs are high in newly generated T cells and low when T cells are absent or when maternally engrafted T cells are present.
SCID is genetically heterogeneous. The most common form in Western countries is inherited as an X-linked trait and is T−B ⁺ NK−.
The lack of all lymphocytes (T−B−NK− SCID) is highly suspicious for ADA deficiency, in which accumulation of toxic metabolites results in death of all lymphocytes. The diagnosis can be confirmed by testing of ADA enzymatic activity and of intracellular levels of phosphorylated derivatives of deoxyadenosine.

Diagnosis by Universal Newborn Screening

SCID can be diagnosed at birth by measuring levels of TCR excision circles (TRECs). TRECs are a byproduct of V(D)J recombination and are present as circularized DNA fragments in newly generated, naïve T lymphocytes that express the αβ form of the TCR. Levels of TRECs in circulating lymphocytes are particularly high in newborns and infants, and can be detected by polymerase chain reaction (PCR) amplification of DNA extracted from the Guthrie card. Newborn screening for SCID was recommended to be added to the standard panel in the United States in 2010, and as of December 2018 all 50 states were screening for SCID. Based on screening of ~3,000,000 infants in the United States, the incidence of SCID is now estimated to be 1 in 58,000 births, higher than with clinical screening alone. Many other countries in the world are also screening.

SCID is not the only cause for low TREC levels at birth; other conditions include prematurity, loss of lymphocytes in the third space (such as in babies with chylothorax) as well as various other syndromes. Enumeration of the absolute lymphocyte count and of lymphocyte subsets (including naïve and memory T cells) should be part of the laboratory work-up following a positive newborn screening concerning for SCID. Ultimately, genetic tests may reveal the molecular basis of the disease.

Prognosis, Therapy, and Future Directions

Supportive Management

Management of SCID includes observance of strict hygiene measures, prevention of P. jiroveci pneumonia with TMP-SMZ, prompt investigation and aggressive treatment of infections, immunoglobulin replacement, and adequate support with enteral or parenteral nutrition. Infections caused by cytomegalovirus (CMV; causing interstitial pneumonia, hepatitis and/or gastroenteritis) and Epstein-Barr virus (EBV; causing lymphoproliferative disease) require active surveillance and preemptive therapy. To prevent transmission of viral infections, blood products from CMV-seronegative donors or leukofiltered products should be used and must be irradiated to prevent transfusion-associated GVHD. Immunosuppression with steroids and cyclosporine A may be needed to treat GVHD-like manifestations associated with Omenn syndrome or maternal T-cell engraftment. Administration of live vaccines must be avoided in infants with SCID. In spite of these measures, SCID is inevitably fatal within the first few years of life, unless immune reconstitution is achieved with treatment.

In most cases, definitive treatment of SCID requires hematopoietic cell transplantation (HCT). Enzyme-replacement therapy (ERT), with weekly intramuscular injection of pegylated recombinant ADA which allows conversion of adenosine and deoxyadenosine to inosine and deoxyinosine, respectively, thus preventing accumulation of toxic phosphorylated derivatives. This treatment leads to improvement of lymphocyte counts and of immune function. Disadvantages of ERT include expense, as it must be continued indefinitely, waning of therapeutic effect over time, and the development in some patients of neutralizing antibodies to polyethylene glycol-modified adenosine deaminase (PEG-ADA).

General Principles of Stem Cell Transplantation for Severe Combined Immune Deficiency

Stem cell transplantation (SCT) is the standard treatment that promotes long-term immune reconstitution in infants with SCID. SCT for other conditions is generally performed with chemotherapy or radiation conditioning, to prevent graft rejection and eliminate or reduce host hematopoietic stem cells (HSCs), favoring donor hematopoiesis. Because of the lack of T lymphocytes, infants with SCID are considered to have an inherent inability to reject the graft, and may therefore receive SCT from an HLA-identical related donor (sibling) without conditioning and with no need for GVHD prophylaxis. With this approach, expansion of mature T cells present in the donor bone marrow allows rapid improvement of T-cell count; newly generated naïve T cells derived from donor HSCs appear on average 3 to 4 months after transplant.

Unconditioned SCT may also be performed from mismatched related donors (parent), with T-cell depletion of the graft and post-transplant prophylaxis to prevent GVHD. In this case, the appearance of peripheral T cells is entirely dependent on intra-thymic differentiation of donor-derived progenitor cells and can take 4 to 6 months.

Following unconditioned SCT for SCID, donor-derived stem cells have a selective advantage over genetically defective autologous HSCs in their capacity to differentiate to T cells. However, failure to obtain robust and durable engraftment of donor HSCs may occur if no conditioning is used. In such cases, after an initial period in which donor-derived committed lymphoid progenitor cells contained in the graft differentiate to T cells, lack of sustained seeding of HSC-derived progenitor cells in the thymus may cause reappearance of severe T-cell lymphopenia and affect the long-term durability and quality of immune reconstitution. For this reason, several centers prefer to perform haploidentical SCT with conditioning. A similar approach is typically followed when performing SCT from matched unrelated adult or cord blood.

While use of conditioning improves the rate of HSC engraftment, it is associated with short-term and long-term toxicity and an increased risk of GVHD, especially when myeloablative regimens are used. These risks may be attenuated by using reduced-intensity conditioning regimens. Finally, non-genotoxic approaches to conditioning with use of monoclonal antibodies (such as anti-CD117) to target the autologous HSCs are currently being evaluated.

Survival and Long-Term Outcomes After Stem Cell Transplantation for Severe Combined Immune Deficiency

Survival after SCT for SCID has improved with time due to advances in early diagnosis and supportive care for infants with SCID. Current figures indicate a 5-year survival that exceeds 90% in the case of SCT from matched sibling donors, and >80% in other cases. It has been demonstrated that age and clinical status at transplantation are the major determinants of survival. In this regard, implementation of newborn screening may facilitate early identification of infants with SCID, prompting adoption of adequate measures to prevent infections and early referral to SCT. Rates of acute and chronic GVHD (aGvHD, cGvHD) are generally low and largely limited to recipients of SCT from donors other than HLA-matched siblings.

The durability and quality of immune reconstitution after SCT depend on multiple factors, including: (1) HLA matching between donor and recipient; (2) use of conditioning regimen; and, (3) the nature of the genetic defect causing SCID. Survivors of SCT performed with a conditioning regimen tend to have higher counts of total and of naïve T-cells than those treated with SCT without conditioning. Among recipients of SCT without conditioning, patients with RAG deficiency have an inferior long-term T cell reconstitution when compared to those with X-linked SCID or JAK3 deficiency or IL7R deficiency. This difference may be due to the fact that RAG deficiency is characterized by the presence of NK cells (which can mediate graft rejection and are absent in patients with X-linked SCID and JAK3 deficiency) and by a later block in intra-thymic T cell development, so that competition between donor-derived and autologous cells occurs during the initial stages of T-cell development. The nature of the genetic defect accounting for SCID may also determine whether use of conditioning regimen may be needed to obtain optimal reconstitution of humoral immunity. Forms of SCID where the genetic defect has no impact on B-cell development and function (such as IL7R deficiency) do not require conditioning, whereas chemotherapy-based preparative regimens that facilitate replacement of autologous HSCs with donor derived cells improve humoral immunity in patients with defects that affect B cell development (RAG deficiency). In the absence of conditioning, inadequate B-cell function (requiring immunoglobulin-replacement therapy) is often observed also in patients with γc and JAK3 deficiency, due to intrinsic defects in the host B-cell response to γc-dependent cytokines such as IL-4 and IL-21. (See box on Therapeutic Approach to Severe Combined Immune Deficiency.)

Patients with poor T-cell reconstitution following SCT are at risk for viral and opportunistic infections; autoimmunity (especially cytopenias and hypothyroidism) has been reported in 10% to 20% of these patients, particularly in those with cGVHD. Other long-term complications include nutritional problems, poor growth and development, and neurologic complications (mental retardation, motor dysfunction, sensorineural hearing deficits). Some of these complications are more common in certain subtypes, particularly growth in patients with Artemis-SCID and neurologic problems in patients with ADA deficiency.

Gene Therapy for Severe Combined Immune Deficiency

Gene therapy, in which the gene of interest is introduced into the patient’s own cells, is an attractive therapeutic option for SCID, in particular for infants who do not have an HLA-identical related donor (see Chapter 104 ). Expression of the normal copy of the gene in CD34 ⁺ stem cells confers a selective advantage to the gene-corrected cells during T-cell differentiation. Furthermore, there is no risk of GVHD. Gene therapy has been used successfully to correct SCID in patients with ADA deficiency and with X-linked SCID.

Since the year 2000, more than 70 patients with ADA-deficient SCID have been treated with gene therapy worldwide. Initial studies have been conducted with transduction of the patients’ CD34 ⁺ cells

Therapeutic Approach to Severe Combined Immune Deficiency

HSC transplantation is the mainstay of treatment. Optimal survival is achieved when the transplant is performed early in life. This is now possible with newborn screening.
Transplantation for SCID can be performed without conditioning, due to the profound absence of T cells and inability to reject. Thus, the bone marrow of a fully HLA-matched sibling can be infused without manipulation and without giving any conditioning to the baby. GVHD prophylaxis is also not necessary. Haploidentical bone marrow from a parent can also be infused without conditioning but generally must be T-cell depleted either ex vivo or in vivo with agents such as cyclophosphamide.
Such transplants without conditioning can result in T-cell reconstitution that lasts for decades. In the case of a matched sibling graft, initial T-cell reconstitution is rapid, generally within the first 1–3 months, due to proliferation of mature T cells. In the case of a haploidentical graft, mature T cells are removed and thus 4–6 months is required for HSC to develop and emerge from the thymus as mature T cells.
Without conditioning, a small number of donor-derived long-lived HSCs engraft, and this may lead to lack of donor B-cell reconstitution and lack of humoral immunity. With conditioning, donor HSCs are more likely to engraft and give rise to donor B cells. Currently, matched unrelated donor transplants are performed with conditioning.
Enzyme replacement may be used in patients with adenosine deaminase deficiency. Gene therapy has offered promising results; however, it is also associated with increased risk of developing leukemia due to insertional mutagenesis.

with gammaretroviral vectors expressing the ADA cDNA. One such vector has received approval as orphan drug by the European Medical Agency. More recently, clinical trials of gene therapy for ADA deficiency have been conducted with use of lentiviral vectors, with great success. Altogether, these experiences have been very successful, leading to sustained production of gene marked T, B and myeloid cells. The majority of patients have been able to stop ERT. Engraftment of gene-corrected stem cells has been facilitated by the use of a reduced-intensity chemotherapy regimen with low-dose busulfan. A single case of T-cell leukemia due to insertional mutagenesis of the retroviral vector has been reported.

Twenty patients with X-linked SCID were treated by gene therapy using a gammaretroviral vector in Paris and London at the turn of the century, without chemotherapy conditioning. Eighteen patients are alive, and 17 of them show normalization of T-cell count and function, with sustained thymic output, diversified T-cell repertoire, and ability to mount antigen-specific T-cell responses. In a few cases, improvement of humoral immunity has also been observed. However, leukemic T-cell proliferation due to insertional mutagenesis was observed in six of these patients, with fatal outcome in one. These serious events have led to the design of new vectors, including self-inactivating gammaretroviral and more recently lentiviral vectors. With these new vectors, successful immune reconstitution has been achieved in treated patients, including older patients who had shown declining immune function after previous SCT. Improved B-cell reconstitution has been achieved in several patients after inclusion of conditioning with low-dose busulfan in the treatment protocol. Importantly, no cases of leukemia have been observed after gene therapy with self-inactivating viral vectors.

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