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Primary immune deficiencies: practical questions

Gouilleux-Gruart, Valérie; Schleinitz, Nicolas; Fischer, Alain

Current Opinion in Allergy and Clinical Immunology: July 2013 - Volume 13 - Issue - p S67–S78
doi: 10.1097/01.all.0000433133.93564.c7
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Valérie Gouilleux-Gruart

‘Efficiency’ of IgG substitution has been evaluated in two cohorts of adult patients with CVID, also known as acquired hypogammaglobulinaemia. One is the French DEFI study cohort (n = 275), managed by Eric Oksenhendler (Paris, France) and the other is the British cohort (n = 105), headed by Helen Chapel (Oxford, United Kingdom). Patients were classified according to the distinct phenotypes outlined by Chapel et al. [135], namely, no complications, autoimmunity, polyclonal lymphocytic infiltration, enteropathy, and lymphoid malignancy. Clinical and biological data are available on patients who have received IgG treatment stably for at least 6 months.

In order to carry out this project, an ‘efficiency index’ was determined in the total of 380 IgG-treated CVID patients from these two cohorts, defined as follows:



The distribution of indices among the 380 patients involved showed variable degrees of efficiency. The study demonstrated that the efficiency index was lower in patients who received IVIg compared with those treated with SCIg. Of note, IVIg doses were 22% higher than SCIg doses [136,137].

The clinical phenotype of the 380 patients (DEFI + Oxford) were divided into two overall groups [135], that included 60% with infections only, whereas the remainder had clinical complications consisting of 26% with lymphoproliferation, 17% with autoimmune cytopenia, and 7% with enteropathy, with a fair amount of patients overlapping between these latter categories. The efficiency index of IgG substitution was evaluated in these patient subgroups divided by clinical phenotype and route of administration. Similarly, IgG substitution was more efficient in SCIg-treated patients compared with IVIg-treated patients, particularly in the patient group with infections only (P < 0.0001). Another noteworthy variable influencing IgG substitution efficiency indices was serum albumin concentrations, as patients who showed reduced IgG efficiency also had low serum albumin levels [136,137].

These data on IgG substitution in CVID patients demonstrated that inferior efficiency was associated with intravenous (i.v.) administration [compared with subcutaneous (s.c.)] and disease-related complications, including enteropathy, autoimmune cytopenia, and nonmalignant lymphoid proliferation. The study also identified low serum albumin as being associated with reduced efficiency of IgG substitution.

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Variability of serum IgG and Fc neonatal receptor gene polymorphism

Several processes may be responsible for the variation of serum IgG concentration. These include an increased volume of distribution, which occurs in haemodilution or hypersplenism, gastrointestinal and urinary leakage, in the context of exudative enteropathy or nephrotic syndrome. A physiopathological phenomenon involved in variation of serum IgG levels also includes catabolism and IgG recycling. Reduced catabolism increases the half-life of IgGs in patients with hypogammaglobulinaemia, reported at 22 versus 38 days [138]. In the 1960s, Brambell et al. [139] hypothesized the existence of a receptor that could bind IgGs and increase their catabolism and half-life. Early publications on serum IgG concentrations led to the description of the key FcRn receptor involved in IgG catabolism and recycling.

The IgG binding FcRn receptor has an important role in humoral immunity. It is a class I-like MHC molecule with a narrow and nonfunctional peptide-binding groove. As such, the FcRn receptor does not present peptides to T-cells [140]. IgG isotype antibodies have an extended serum half-life and can cross cell barriers, properties which are conveyed by FcRn. The clinical and therapeutic implications remain to be fully described.

The FcRn receptor has multiple functions and is ubiquitously distributed, probably at varying concentrations. FcRn plays a central role in IgG transport across placental barriers. This receptor also binds albumin, at a completely different binding site to IgGs. The differential FcRn binding to IgG and albumin ligands is pH-dependent [141]. Because of FcRn's role as an intracellular transport protein, it affects serum protein half-life, transcytosis, and protein recycling. In addition to these functions, two more recently described functions of FcRn are gaining in importance. First, FcRn has been implicated in phagocytosis of immune complexes [142]. Second, the receptor has been shown to have a role in antigen presentation and B-cell-mediated humoral response (not via the peptide binding groove) [143,144]. In the context of immunoglobulin substitution therapy, FcRn therefore is a key partner [145].

FcRn is coded by the FCGRT gene, located on chromosome 19 in humans [146]. Genetic variations of FcRn-dependent transport may affect antibody-mediated disorders. A region of variable number of tandem repeat (VNTR) polymorphisms has been described in the FcRn promoter, consisting of up to six repetitions of a 37 bp motif [147]. Monocytes isolated from VNTR3 (alleles with three repeats) homozygous individuals were associated with significantly higher FcRn expression compared with monocytes isolated from VNTR2/VNTR3 heterozygous individuals (P = 0.002). In addition, significantly increased binding to polyvalent human IgG was observed in monocytes from VNTR3 homozygotes compared with VNTR2/3 heterozygous individuals (P = 0.021). The impact that interindividual variation of FcRn expression may have, and the way in which differential expression of FcRn influences IgG-dependent disorders remain to be fully elucidated.

The hypothesis that the VNTR polymorphism may influence the efficiency of IgG substitution is currently under investigation in the CVID patient cohort [136,137]. Preliminary DNA analyses have shown that the distribution of VNTR alleles in CVID patients is identical to that of the control population, in that alleles with two (VNTR2) and three (VNTR3) repeats were found to be most common. The efficiency index of IgG substitution was measured according to FCGRT genotype, and the outcome showed that VNTR3 homozygotes had better IgG efficiency versus VNTR2/3 heterozygotes, in agreement with the data presented by Sachs et al. [147]. In VNTR3 homozygous individuals, IgG substitution was more efficient compared with other genotypes, regardless of method of administration.

In conclusion, in patients with CVID, IgG substitution is monitored by serum IgG trough levels. An IgG replacement therapy efficiency index was defined as the ratio of serum IgG trough level minus IgG residual (g/l) to the average weekly dose of IgG infusion (g/kg per week). A study in 380 CVID patients from two prospective cohorts has investigated factors influencing the dosage required to achieve sufficient IgG trough levels [136].

The VNTR3/VNTR3 FCGRT genotype is the most frequent in the general population and in CVID patients. This genotype is associated with increased binding to polyvalent IgGs [147], and may ensure optimal recycling. In CVID patients with a different genotype to VNTR3/VNTR3, the efficiency of IgG substitution is lower, an effect that appears more pronounced in patients substituted intravenously. A proposed hypothesis explaining this difference is that IVIg administration may saturate FcRn receptors and cause increased IgG catabolism and half-life, an effect that is not observed with SCIg use. Indeed, no strong peak IgG concentrations are observed following SCIg administration, in which serum IgG are more stable, probably below the FcRn saturation threshold.

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Nicolas Schleinitz

Immunoglobulin substitution was first administered intramuscularly (i.m.) in the 1950s, and intravenous substitution (IVIg) was first introduced in a hospitalized environment in the 1970s. Slow home-based SCIg substitution was introduced in the 1980s, whereas home-based IVIg substitution started in 1999. For reasons of differing legislation and product availabilities, the modalities of immunoglobulin substitution have been very heterogeneous from one country to another. In France, the marketing authorization for IVIg substitution at home was obtained in 2002, and in 2005 for home-based SCIg.

In 2006, a survey from the IRIS association (French PID patients association, reported that the proportion of PID patients receiving home-based IVIg substitution increased dramatically since the advent of SCIg in 2005: almost two thirds of individuals were treated at home, and a third were treated in hospital. A minority of patients either alternated between home-based and hospital-based treatment, or were undergoing training in order to receive home-based treatment. All SCIg treatments occurred at home, compared with a majority of i.v. substitutions in hospital. In our single centre experience in 60 PID patients receiving immunoglobulin substitution, half have been treated with home-based SCIg since 2005. Thus, the s.c. modality has had a considerable impact on the management of PIDs, by facilitating home-based treatment. However, a nationwide survey by the French national registry of primary immunodeficiency diseases in 2009 reported that IVIg was still used in the majority of patients: 74% IVIg versus 26% SCIg in 1112 PID patients receiving immunoglobulin replacement therapy [148].

Nowadays, an increasing number of modalities and choices are made with patients and their close contacts, on whether to prescribe hospital-based or home-based IVIg, or home-based SCIg. Factors influencing choices include frequency of administration, volumes administered, and the use of pumps or of the rapid push technique [149]. The medical objective is to ensure prevention of infectious complications with optimal comfort and quality of life for patients, while taking into account societal constraints and costs.

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In an international, multicentre, open-label, crossover study, Chapel et al. [150] compared the ability of IVIg versus SCIg immunoglobulin replacement therapy to prevent infections in 40 PID patients over a 2-year period. The study concluded that IVIg and SCIg protection conferred comparable efficacy in these patients. The efficacy of both administration routes has since been largely been confirmed.

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Few adverse effects are associated with IgG treatment, regardless of administration route. Adverse effects observed with IVIg administration have mainly occurred in the immunomodulation setting (in which higher doses are used compared with immunosubstitution, e.g. 2 g/kg per month), as seen by fluctuating IgG serum levels [151]. Adverse reactions observed in the initial crossover study were mild-to-moderate, with a frequency of 5.4% for IVIg compared with 10.4% with SCIg (or 3.3% when local transient reactions were excluded) [150]. Thus, both treatment modalities are well tolerated, with perhaps fewer systemic reactions with SCIg use. The following intolerance reactions to IVIg may be reasons for switching to SCIg administration, or for favouring SCIg: aseptic meningitis, poor renal tolerability (in the immunomodulation setting), thromboembolic disorders, marked ‘systemic’ reactions, independent of speed of administration, or the presence of anti-IgA antibodies with systemic manifestations.

Patients with anti-IgA antibodies were described early in the field of immunoglobulin substitution. An anaphylactoid transfusion reaction associated with anti-IgA observed after i.m. IgG administration was reported in a patient with complete IgA deficiency who developed anti-IgA IgGs [152]. The frequency of class-specific anti-IgA IgGs was calculated at 24–32% in IgA-deficient patients. Among 325 CVID patients deficient in IgG2 and IgA, more than 30% had anti-IgA IgGs (all with severe IgA deficiency). Frequency of anti-IgA IgE was lower, most often associated with anti-IgA IgGs. Of note, there is considerable variability in the sensitivity of antibody detection techniques, which at times may complicate the comparison of results from one study to another [153].

Among patients with anti-IgA antibodies who experienced anaphylactoid reactions, no deaths has been reported (although this may be due to publication bias). Anaphylactoid reactions usually occur in adults with a severe IgA deficiency (<10 mg/dl) who have class-specific anti-IgA IgGs. All cases have been recorded after i.v. or i.m. administration. In these patients, SCIg administration is well tolerated. The role of anti-IgA antibodies in anaphylactoid reactions has been challenged, as the majority of patients with anti-IgAs tolerate i.v. and i.m. IgG well. Without necessarily systematically searching for anti-IgA antibodies, it is generally accepted that patients who experience anaphylactoid reactions after IVIg administration should be switched to SCIg [153].

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Pharmacokinetics: intravenous versus subcutaneous

As previously mentioned, IVIg treatment is associated with fluctuations in serum IgG concentrations, with elevated peak and low trough levels that may be responsible for some secondary effects in immunomodulation (IgG variation rate of higher than 75 versus ±2.5%, respectively) [151]. The half-life of IVIg is 21–28 days compared with 40 days with SCIg [154], which may impact on the dose administered and on costs.

Studies have suggested that efficiency of SCIg substitution is superior to IVIg. In 65 patients with primary hypogammaglobulinaemia receiving IVIg replacement, IgG trough levels were measured at baseline and during 1 year following a switch to SCIg treatment. Median serum IgG levels in patients on IVIg and just before the initiation of SCIg at baseline was 8.37 g/l (range, 4.2–17.7). The mean value for serum IgG after 12 months of SCIg therapy was 8.82 g/l (range, 3.5–17.8), representing a 5.4% increase (nonsignificant), despite a lower immunoglobulin dose reduced by 28.3% (151–108 mg/kg per week, P < 0.0001) [155]. This study did not show a difference on overall infection rate in patients.

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Treatment cost considerations

Considering that long-term replacement therapy is required in most PID patients, treatment costs are a concern. The cost-effectiveness of SCIg versus IVIg was compared in a French study, including the variable of whether treatment was administered at home or in an outpatient setting. Estimations on field data including mean immunoglobulin, hospital, nursing and infusion pump/kit costs, found that the total mean costs per year for SCIg treatment was 25% less than for IVIG [156]. The lower cost reported for SCIg replacement therapy was attributed to lower immunoglobulin mean dose prescribed for SCIg. However, in this study, statistical significance was not reached for monthly dose per weight unit between SCIg and IVIg.

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Subcutaneous immunoglobulin treatment modalities

The choice of two ambulatory programmable infusion pumps for SCIg administration is available in France, namely the Chrono PID 20 and 50 (Pentaferte), which differ in syringe volume (20 or 50 ml). Administration is typically given on a weekly basis. As some patients find infusion pumps difficult to use, and these may add to treatment costs, the rapid push technique has been proposed as a more convenient alternative. Rapid push relies on using a syringe and a 23–25-gauge butterfly needle to push SCIg under the skin as fast as the patient is comfortable with (usually 1–2 ml3/min up to 20 min). The frequency of administration varies depending on patient requirements and preference (every day or three times a week) [157]. Shapiro [149] reported their experience in a cohort presented with a choice between rapid push and pump administration. The study suggested that rapid push was preferred to standard pump infusion. Neither method showed disparities in serum IgG levels or safety. The authors noted that confirmation in prospective studies is warranted. The frequency of administration is another point of concern to patients, who may prefer to administer injections every other week rather than on a weekly basis [157].

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Route of administration and hospital-based versus home-based treatment

The choices of which treatment modality to use is discussed and adapted on an individual basis with patients and their close contacts. The information provided must be exhaustive. It is important for the patient to understand that these choices are not irreversible. Several requirements are needed of patients who elect to use home IVIg administration. The patient must be stabilized, capable of autonomy, display good tolerability during the initial trial period, and must have received 6 months of previous hospital-based IVIg treatment.

A series of ‘medical prerequisites’ must also be in place in order to implement SCIg replacement therapy. Indeed, patients are required to undergo a training programme for s.c. administration. A network of suppliers or home-based hospitalization services must therefore be in place, along with facilities for consultation, medical follow-up and nursing of patients substituted at home.

The pros and cons of immunoglobulin route of administration and hospital-based versus home-based treatment are outlined in Tables 5 and 6.

Table 5

Table 5

Table 6

Table 6

From a practitioner's perspective, hospital-based treatment offers greater safety, for both patients and practitioners. It also affords the opportunity to follow patients with rare diseases and to maintain an activity and gain experience in the field. In some cases, hospital-based therapy may be the only available choice, in the absence of a training programme or of a network of healthcare practitioners required to implement home-based therapy. From the point of view of a treating physician, home-based therapy could be seen as a disadvantage, for fear of losing patients to referral centres, or of completely losing track of patients. On the contrary, home-based treatment may help build a relationship of trust between the practitioner and the patient. Moreover, home-based replacement therapy relieves outpatient services, and some practitioners believe that patients receive better follow-up during consultation rather than in an outpatient setting. Still from the viewpoint of physicians, the choice of whether to administer i.v. or s.c. can be influenced by a number of factors. Intravenous administration may be preferred as a result of the physician's experience, and to the fact that it is feasible in all patients, except in rare cases of patients with severe complications. This treatment modality achieves required IgG levels faster than SCIg. Disadvantages of IVIg use may be the presence of anti-IgA antibodies, or the occurrence of severe reactions regardless of anti-IgA antibodies. In contrast, elements that may influence decision making towards the use of SCIg are the ease of administration at home, the achievement of stable and possibly higher serum IgG levels, fewer adverse effects overall, and good tolerability in patients with anti-IgA antibodies.

In summary, the medical objective of immunoglobulin substitution is to optimize prevention of infectious complications and quality of life in patients, while taking into account societal costs and constraints. Studies have demonstrated that both s.c. and i.v. treatment modalities are equivalent in terms of efficacy, and that SCIg may have a positive impact on patient quality of life. In terms of treatment costs, new s.c. administration modalities (infusion pumps, rapid push or concentrated s.c. preparations) have yet to be investigated in prospective studies, to confirm that SCIg is cheaper compared with IVIg, due to the lower immunoglobulin doses prescribed. To date, the choice of the modalities of substitution relies on patient's choice after complete and clear medical information. In this context, it is important to train healthcare practitioners, patients and their close contacts for home-based immunoglobulin substitution to make this choice possible. Implementation of successful home-based treatment requires appropriate education, training, and supportive care.

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Alain Fischer

In order to optimize management of patients with PIDs, an improved understanding of the disease physiopathologies is necessary. The better these mechanisms are understood, the better the chances are of providing adequate efficacious treatment. An overview of treatment strategies in patients with PIDs is provided below.

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Protein supplementation

The most commonly used treatment is by far IgG substitution, although IgGs are far from being the only effectors involved. Distinct immune deficiencies develop at different timepoints in the differentiation of B-cells [158]. For instance, agammaglobulinaemia develops at an early stage of B-cell differentiation, whereas hyper-IgM syndrome (HIgM), CVID, or IgA deficiency occurs at later stages.

A much less frequent protein supplementation option includes parenteral adenosine deaminase (ADA) injection in severe combined immunodeficiency (SCID) [159]. In the case of very rare cytokine deficiencies, such as IL-17F, secreted by Th17 cells, and which is deficient in some hereditary forms of chronic mucocutaneous candidiasis (CMCC) [160], one can imagine that IL-17 treatment may be developed to treat these patients. Similarly, IL-10 substitution may treat IL-10 cytokine deficiency in paediatric patients who develop severe infantile (very early onset) inflammatory bowel disease [161]. Therefore, as more light is shed on the molecular mechanisms underlying these diseases, the greater are the hopes of optimizing treatment for these patients.

As a physiological reminder, IgA and IgM are exported to the lumen of mucosal surfaces [162], of which there are three categories: the bronchus-associated, nasopharynx-associated, and gut-associated lymphoid tissues. At each mucosal surface, different antibody isotypes with different immunological properties are present. Dimeric IgAs and IgM are transported across the epithelium (trancytosis) and are secreted to confer antimicrobial protection, for example in the colon. Of note, IgGs do not share this property and can be secreted and transported through the mucosal epithelium. Thus, IgMs may have a potential role against infection by virtue of their secretory properties.

Despite adequate immunoglobulin replacement therapy, primary immunoglobulin deficiencies lead to recurrent respiratory tract bacterial infections and bronchiectasias. A prospective study compared infectious/microbiological events in patients who either had panhypogammaglobulinaemia (PHG, in which IgM production is lacking) or who retained the ability to secrete IgM (e.g. those with HIgM syndrome), in order to assess whether the presence of IgM conferred a protective role [163]. Micol et al. performed regular nasal swabs and sputum analyses, and recorded clinical events in patients with HIgM syndrome (n = 25) and patients with PHG (n = 86) who received similar immunoglobulin replacement therapies for 2 years. Serum and saliva IgM antibody concentrations were also measured. The study reported that more PHG patients developed chronic sinusitis and bronchiectasias (significant for bronchiectasias) compared with HIgM patients. Analyses of nontypeable H. influenzae (NTHi) carriage showed that HIgM patients were significantly more likely to be NTHi-free compared with PHG patients (RR 0.39, 95% CI, 0.21–0.63, P = 0.012). Patients with HIgM syndrome displayed anti-NTHi serum and saliva IgM antibodies. Finally, HIgM patients had a lower risk of acute respiratory tract infections compared with PHG patients over the 2-year study period: RR 0.24, 95% CI 0.13–0.47.

These data suggest that IgM antibodies have a protective role against infections at mucosal surfaces (e.g. NTHi, enterovirus, etc.). Therefore, not all hypogammaglobulinaemic patients are equal. Naturally, IgG therapy confers protection, but it might not fully compensate for IgM deficiency. These data may lead to a reflection on whether therapy should in future be more specific according to the underlying PID, and for instance be completed with additional agents (e.g. antibiotics) [163].

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Bypassing cellular defects

In the analysis of PIDs based on the study of disease mechanisms, treatment strategies in addition to protein supplementation include methods that bypass cellular defects. For instance, granulocyte colony-stimulating factor significantly prevents severe infections in patients with severe congenital neutropenias [164]. Other examples include the use of IFN-α in herpes simplex virus infection, or of IFN-γ in Mendelian susceptibility to mycobacterial diseases [165,166].

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Neutralization of cytokines

A third strategy consists in neutralizing potentially toxic excess cytokines. This has been most convincingly demonstrated with anti-IL-1 in chronic infantile neurological cutaneous and articular syndrome, which is the only clinically available example that allows considerable reduction of chronic inflammation, entirely based on an improved understanding of the disease's physiopathology [167,168]. Other examples include the use of anti-IFN-γ in haemophagocytic lymphohistiocytosis (HLH), or possibly of anti-STAT-1 in CMCC, as summarized below.

Haemophagocytic lymphohistiocytosis is caused by accumulation of CD8+ T-cells and natural killer cells that proliferate and infiltrate tissues, producing large quantities of IFN-γ. In this disease, CD8+ T-cells are deficient in the exocytosis of cytotoxic granules and are unable to kill infected targets. The model for HLH proposes that overstimulation of adaptive immunity leads to disease progression. Continuous antigen stimulation from infected antigen-presenting cells to CD8+ T-cells causes IFN-γ overproduction that activates macrophages, which secrete other cytokines (IL-6, TNF-α, or IL-18) involved in tissue damage [169,170]. There are therefore valid reasons to believe that IFN-γ is an important HLH marker/disease target, as it has been reported to be increased in both inherited and acquired HLH, as seen from serum levels and biopsies [171,172]. Evidence suggesting that IFN-γ may have pathogenic properties was provided in a murine HLH model, which showed that IFN-γ neutralization prevented occurrence of HLH in lymphocytic choriomeningitis virus (LCMV)-infected perforin-deficient mice [169].

Similar HLH murine models (perforin-deficient and Rab27a-deficient mice infected with LCMV) have shown that administration of anti-IFN-γ antibody 8 days after infection had a therapeutic effect and induced HLH recovery. Upon anti-IFN-γ treatment, perforin-deficient mice displayed improved survival and clinical and haematological recovery, improved bone marrow aplasia, restored spleen architecture, and reduced macrophage activation in the liver. Together, these data suggest that anti-IFN-γ could be used in the clinic [173], and may offer more benefit than the currently available aggressive therapies in use against HLH (e.g. etoposide, antithymocyte globulin) [174]. Clinical trials of anti-IFN-γ reagents have not yet been initiated, but such a targeted approach may confer positive results.

A theoretical suggestion for a treatment strategy in which cytokines could be neutralized in PIDs, is the inhibition of STAT-1 to treat CMCC. A recent study reported that the majority of patients with dominant CMCC had defects in the STAT-1 transcription factor [175]. Among CD4+ T-cells, some differentiate into Th17 lymphocytes, which secrete IL-17F, a cytokine with protective activity against cutaneous and mucosal fungal infections. The effector and regulatory elements modulating T-cell differentiation from naive CD4+ cells to Th17 cells are involved in immunity against Candida. These effector and regulatory factors depend on STAT-1 expression, and chronic candidiasis can be caused by a gain of function mutation in STAT-1. The mutated mSTAT-1 may block differentiation from naive CD4+ T-cells to Th17 cells, with the result that patients fail to develop effective immunity against Candida. STAT-1 inhibitors are in development in other unrelated indications. It is believed that an adapted dose would allow to redress the balance towards efficient immunity against Candida, once again providing a potentially improved treatment option in these patients who rely on antifungal therapy that is toxic with long-term use.

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Cell therapy

Two types of cell therapy are used in the treatment of PIDs. The predominant therapy is the use of haematopoietic stem cell transplantation (HSCT). Thymus grafts are also performed in some patients with genetic disorders affecting thymus development (e.g. Di George syndrome), in which the nonepithelial component is used.

Over approximately 40 years of experience worldwide, thousands of PID patients with potentially fatal disorders have received allogeneic HSCT, with varying degrees of success. For instance, in disorders of the innate immune system, treatment of patients with T-cell disorders, or deficiencies in leucocyte adhesion (integrin β 2) protein expression, or chronic granulomatous disease is increasingly frequent. These disorders are curable with allogeneic HSCT because abnormal neutrophils (either in their adhesion capacity or their ability to kill bacteria) are replaced with normal functional neutrophils. The same can be said for HLH conditions.

Based on data from a European database 1970–2005 [176], the progress in allogeneic HSCT survival outcomes was evaluated in patients with SCID, one of the most severe forms of immune deficiency. Depending on the donor, patient survival was between approximately 60% [partially incompatible human leukocyte antigen (HLA), parent] and 90% (genetically identical HLA). The analysis showed that no improvement in survival has been made with parental donors in recent years (2000–2005) compared with earlier data (1995–1999), an outcome that was considered disappointing. Postallogeneic HSCT survival was investigated in all other immune deficiencies included in the study (Wiskott–Aldrich syndrome, phagocytic cell deficiencies, HLH, and T-cell deficiencies). Wiskott–Aldrich syndrome patients had the best survival rates (71%), followed by patients with phagocytic cell deficiencies (63%), HLH (58%), and T-cell deficiencies (47%). In analysing the overall success and failure of allografts over time, survival in patients with these disorders (excluding SCID) has improved from 55% before 1995 to 58% between 1995–1999 and up to 74% between 2000–2005. Survival rates following allogeneic HSCT have improved, but there is room for further improvement, particularly in preventing graft versus host disease (GVHD) and infections.

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Gene therapy

For patients who lack a suitable HLA-matched donor, gene therapy is an attractive alternative treatment option. The rationale for this approach is that GVHD and preconditioning may be altogether bypassed. The approach consists in inserting the correct gene into patients’ haematopoietic stem cells (HSCs) via virus-based vectors that can permanently integrate genomic DNA to drive long-term expression of corrective genes in HSC lineages. This strategy has been in development in patients with immune deficiencies since the late 1990s, essentially for two forms of SCID: X-linked severe combined immunodeficiency (SCID-X1, in which T-cells and natural killer cells are absent) and ADA deficiency (ADA-SCID, in which there is a complete absence of lymphocytes).

Bone marrow cells from patients with no HLA-matched donor were infected ex vivo with the amphotropic MFGB2 retroviral vector containing the therapeutic gene (gamma-c IL-2 receptor subunit). Transduced CD34+ cells were then re-injected into patients. Compared with allogeneic HSCT, gene therapy has demonstrated excellent survival rates based on results from two SCID-X1 (n = 20) and three ADA trials (n = 35), even though with some major safety caveats [177–179].

Among 20 SCID-X1 patients treated between 1999 and 2005, 18 are alive, with 85% disease-free survival, a median follow-up of 9.6 years (5.0–12.8 years), and a functional immune system. The data are, however, far from perfect because five patients developed serious adverse events (including one fatal) in the form of leukaemia that led to trial interruption. Indeed, it was found that insertional activation of proto-oncogenes by the integrated proviral vectors caused clonal expansion and leukaemia. The trials have been restarted, using modified self-inactivated vectors that should no longer cause this complication, with the added objective of investigating this approach in other disorders. In a total of 35 treated ADA-SCID patients, all are alive and have a functional immune system (median follow-up 4.7 years, 1.0–10.9 years), but 31% still require enzyme replacement therapy. No serious adverse events were observed in the ADA-SCID patients.

In summary, a wide array of therapeutic approaches is available to treat PIDs, and further approaches are in development. Other examples of strategies include stabilization of gain of glycosylation mutations, or suppression of premature termination and nonsense mutations, such as has been investigated (with modest success) in cystic fibrosis. The choice of therapies and strategies will increase as our understanding of the molecular mechanisms involved in these disorders becomes clearer.

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Conflicts of interest

S. Kaveri has received grants, honoraria, and travel reimbursements from CSL-Behring and travel reimbursements from LFB France. L. Guillevin has no conflicts of interest to declare. L. Mouthon has received honoraria from and provided consultancy for CSL-Behring, received fees for board membership, and travel reimbursement from and providided consultancy for LFB Biotechnologies, and has provided consultancy for Octapharma. J.-P. Fermand has received honoraria from CSL-Behring. J.-E. Gottenberg has no conflicts of interest to declare. V. Gouilleux-Gruart has received grants and travel reimbursement from CSL-Behring. N. Schleinitz has a pending grant and has received oayments for lectures from CSL-Behring. A. Fischer has no conflicts of interest to declare.

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