Severe Asthma and Biologics: Managing Complex Patients.

Bronchial asthma is a chronic inflammatory disease of the respiratory tract that varies in terms of clinical presentations (phenotypes) and distinct underlying pathophysiological mechanisms (endotypes). The definition of phenotype/endotype is crucial, given the availability of novel biologic agents for patients who do not respond to conventional therapies. Although patients with type 2 severe asthma benefit significantly from treatment with biologics, nonresponders have been identified. Comorbidities worsen the symptoms of asthma and complicate management of the disease. The assessment and treatment of comorbidities is a crucial step, and appropriate management may improve asthma symptoms and morbidity. Among comorbidities, those with a marked negative impact on control despite appropriate treatment include chronic rhinosinusitis with nasal polyps, obesity, bronchiectasis, and immune deficiency. Although asthma is frequently characterized by increased blood eosinophils that release mediators and cytokines and are involved in inflammation of the airway wall, in patients with very high blood eosinophil levels, we must differentiate between isolated severe eosinophilic asthma and asthma in eosinophilic granulomatosis with polyangiitis. In addition, hypereosinophilia may result from specific biological treatment, as in the case of dupilumab. We outline the clinical features of patients with severe asthma whose disease is complex to manage.

IgG4 anti-infliximab in treated patients: Clinical impact and temporal evolution.

BACKGROUND: Infliximab (IFX) carries potential risk of immunogenicity with the production of anti-drug antibodies (ADA). ADA may belong to different isotypes and are usually measured by ELISA bridging assay. This test is not designed to detect IgG4 antibodies. The aim was to measure IgG4 anti-IFX antibodies in a cohort of IFX-treated patients and to evaluate their relationship with ADA and their clinical impact. METHODS: Anti-drug antibodies were detected using a bridging ELISA in the serum of 222 treated patients with different clinical outcomes to IFX. The same samples were analyzed for IgG4 anti-IFX antibodies using an experimental ImmunoCAP assay with reduced serum IgG4 background levels. A longitudinal evaluation was performed in a subgroup of 38 patients to define the temporal evolution of IgG4 anti-IFX. RESULTS: IgG4 anti-IFX was found in 26.6% of patients. Eighty of 222 patients were ADA+ (36%) and the majority (57/80, 71.3%) had IgG4 anti-IFX. Two IgG4-positive but ADA-negative patients were identified. IgG4 anti-IFX levels correlated with the serum levels of ADA. IgG4 anti-IFX was more common in both reactive and nonresponder patients than in tolerant/responder patients. Patients who had experienced IgE-mediated reactions displayed significantly higher IgG4 anti-IFX than IgE-negative reactive patients. The majority of patients tested positive for IgG4 anti-IFX after the first seven infusions. CONCLUSIONS: IgG4 anti-IFX is common in treated patients and a large part of ADA producing patients produce IgG4 antibodies. The IgG4 anti-IFX response does not prevent hypersensitivity reactions to IFX and correlates with the IgE anti-IFX response.

Circulating T cells to infliximab are detectable mainly in treated patients developing anti-drug antibodies and hypersensitivity reactions.

Antibodies recognizing infliximab (IFX) may develop in a proportion of treated patients, leading to loss of response or hypersensitivity reactions (HRs). T cell response to IFX has been poorly investigated. This paper was addressed to detect IFX-specific T cells in treated patients with inflammatory diseases developing, or not, anti-drug antibodies (ADA) and to correlate the presence of specific T cells with the clinical outcomes of the treatment. A co-culture system of IFX-loaded dendritic cells and purified autologous CD4+ T cells was used to detect memory T cells in 32 ADA+ and 39 ADA- IFX-treated patients and control groups. The cytokine profile of IFX-specific T cells was also studied in culture supernatants. IFX-specific cell proliferation was detected mainly in cells from ADA+ patients, irrespective of their different diseases. HR patients displayed higher T cell proliferation than non-responder and tolerant patients. A mixed [interferon (IFN)-γ, interleukin (IL)-13, IL-10] cytokine profile was shown in cells from ADA+ patients, while IL-10 was the most frequently detected cytokine in the supernatants of cultures from ADA- patients. Immunoglobulin (Ig)E+ ADA+ patients with previous HRs exhibited a more pronounced type 2 profile than IgE- ADA+ patients. This work provides evidence that IFX-specific circulating T cells are detectable mainly in ADA+ patients with HRs, regardless of their disease. The IFX-induced cytokine pattern partially correlates with the ADA isotype.

In vitro tests for drug hypersensitivity reactions: an ENDA/EAACI Drug Allergy Interest Group position paper.

Drug hypersensitivity reactions (DHRs) are a matter of great concern, both for outpatient and in hospital care. The evaluation of these patients is complex, because in vivo tests have a suboptimal sensitivity and can be time-consuming, expensive and potentially risky, especially drug provocation tests. There are several currently available in vitro methods that can be classified into two main groups: those that help to characterize the active phase of the reaction and those that help to identify the culprit drug. The utility of these in vitro methods depends on the mechanisms involved, meaning that they cannot be used for the evaluation of all types of DHRs. Moreover, their effectiveness has not been defined by a consensus agreement between experts in the field. Thus, the European Network on Drug Allergy and Drug Allergy Interest Group of the European Academy of Allergy and Clinical Immunology has organized a task force to provide data and recommendations regarding the available in vitro methods for DHR diagnosis. We have found that although there are many in vitro tests, few of them can be given a recommendation of grade B or above mainly because there is a lack of well-controlled studies, most information comes from small studies with few subjects and results are not always confirmed in later studies. Therefore, it is necessary to validate the currently available in vitro tests in a large series of well-characterized patients with DHR and to develop new tests for diagnosis.

EAACI IG Biologicals task force paper on the use of biologic agents in allergic disorders.

Biologic agents (also termed biologicals or biologics) are therapeutics that are synthesized by living organisms and directed against a specific determinant, for example, a cytokine or receptor. In inflammatory and autoimmune diseases, biologicals have revolutionized the treatment of several immune-mediated disorders. Biologicals have also been tested in allergic disorders. These include agents targeting IgE; T helper 2 (Th2)-type and Th2-promoting cytokines, including interleukin-4 (IL-4), IL-5, IL-9, IL-13, IL-31, and thymic stromal lymphopoietin (TSLP); pro-inflammatory cytokines, such as IL-1ß, IL-12, IL-17A, IL-17F, IL-23, and tumor necrosis factor (TNF); chemokine receptor CCR4; and lymphocyte surface and adhesion molecules, including CD2, CD11a, CD20, CD25, CD52, and OX40 ligand. In this task force paper of the Interest Group on Biologicals of the European Academy of Allergy and Clinical Immunology, we review biologicals that are currently available or tested for the use in various allergic and urticarial pathologies, by providing an overview on their state of development, area of use, adverse events, and future research directions.

Effects of benralizumab in patients with severe eosinophilic asthma (SEA): A plain language summary of the ANANKE study.

WHAT IS THIS SUMMARY ABOUT?: This summary outlines the findings from the ANANKE study on the treatment of patients with severe eosinophilic asthma (SEA) with benralizumab. SEA is an inflammatory disease of the lungs caused by eosinophils. Patients with SEA may experience asthma attacks (exacerbations) and decreased ability to breathe (lung function) despite taking medications. Benralizumab (Fasenra®) is a biologic therapy (a medicine produced using living cells) approved for the treatment of SEA.The ANANKE study was conducted in Italy and evaluated the characteristics of patients with SEA who received benralizumab as prescribed by their doctors. It also described the effects of benralizumab on participants in terms of frequency of exacerbations, lung function and overall control of asthma, and their need to take oral corticosteroids (OCS) to control symptoms. The effects of benralizumab have been observed in participants treated for: 1) an average of 10.3 months, and 2) up to 96 weeks (approximately 2 years). The effects were also compared between different groups: 1) participants with chronic rhinosinusitis with nasal polyps (CRSwNP) and those without, and 2) participants who received other biologics before benralizumab (bio-experienced) and those who started with benralizumab as their first biologic (naïve). CRSwNP is an inflammatory condition that makes breathing even more difficult. WHAT WERE THE KEY FINDINGS?: Before receiving benralizumab, participants showed a high blood eosinophil count (the number of eosinophils in the bloodstream), frequent exacerbations, insufficient lung function, and poor disease control (symptom management). After 96 weeks, benralizumab almost eliminated exacerbations, improved lung function, reduced the use of OCS, and increased the control of SEA symptoms while lowering blood eosinophil count. Comparable effects were observed between participants with and without CRSwNP and between naïve and bio-experienced participants. WHAT WERE THE MAIN CONCLUSIONS REPORTED BY THE RESEARCHERS?: The ANANKE study showed that participants had frequent exacerbations and were characterized by eosinophilic inflammation before starting benralizumab. Overall, benralizumab improved the control of the disease for up to 2 years and induced similar beneficial effects regardless of the presence of CRSwNP and the use of previous biologics. These findings highlight the long-lasting and broad action of benralizumab.Clinical Trial Registration: NCT04272463 (ANANKE) (ClinicalTrials.gov).

Allergological in vitro and in vivo evaluation of patients with hypersensitivity reactions to infliximab.

BACKGROUND: The administration of biological agents is potentially affected by IgE-mediated infusion reactions. OBJECTIVE: The aim of the study was to evaluate the utility of skin testing in patients who have experienced infliximab (IFX)-related reactions. METHODS: Thirty patients with previous immediate hypersensitivity reaction to IFX, 20 disease-matched non exposed subjects, 15 IFX-treated disease-matched tolerant patients and 15 IFX non-responder patients were enrolled. Non-isotype-specific and IgE anti-drug antibodies (ADAs) were measured by a double-capture ELISA kit and ImmunoCAP assay, respectively. Prick and intra-dermal tests were carried out with the commercial IFX preparation serially diluted. RESULTS: Skin testing, performed in 23 of 30 reactive patients, resulted positive in 7 of them (30.4%), whereas no positivity was found in other groups of patients. The majority of reactive patients displayed non-isotype-specific ADAs (23/30, 76.6%) and the presence of anti-IFX IgE antibodies was detected in 6 of them (26%). All 6 IgE-positive reactive patients showed skin testing positivity. One reactive ADAs-positive patient who resulted skin test positive, with no detectable serum IFX-specific IgE ADAs, was also found. Skin testing positivity was associated with severe and early reactions (within the 3rd dose). No unexpected adverse reactions to skin testing were recorded. CONCLUSIONS AND CLINICAL RELEVANCE: This study shows that about 30% of reactive patients display skin testing positivity. They usually develop severe reactions, mainly during the first administrations of IFX. The specificity and the safety of skin testing procedure for this biological agent are also confirmed.

Case Report: A child with NFKB1 haploinsufficiency explaining the linkage between immunodeficiency and short stature.

We report the case of a patient with common variable immunodeficiency (CVID) presenting with short stature and treated with recombinant human growth hormone (rhGH). Whole exome sequencing revealed a novel single-nucleotide duplication in the NFKB1 gene (c.904dup, p.Ser302fs), leading to a frameshift and thus causing NFKB1 haploinsufficiency. The variant was considered pathogenic and was later found in the patient's mother, also affected by CVID. This is the first reported case of a patient with CVID due to NFKB1 mutation presenting with short stature. We analyzed the interconnection between NFKB1 and GH - IGF-1 pathways and we hypothesized a common ground for both CVID and short stature in our patient.

Genome-wide association study of serious blistering skin rash caused by drugs.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but severe, potentially life threatening adverse drug reactions characterized by skin blistering. Previous studies have identified drug-specific and population-specific genetic risk factors with large effects. In this study, we report the first genome-wide association study (GWAS) of SJS/TEN induced by a variety of drugs. Our aim was to identify common genetic risk factors with large effects on SJS/TEN risk. We conducted a genome-wide analysis of 96 retrospective cases and 198 controls with a panel of over one million single-nucleotide polymorphisms (SNPs). We further improved power with about 4000 additional controls from publicly available datasets. No genome-wide significant associations with SNPs or copy number variants were observed, although several genomic regions were suggested that may have a role in predisposing to drug-induced SJS/TEN. Our GWAS did not find common, highly penetrant genetic risk factors responsible for SJS/TEN events in the cases selected.

Poly(I:C) promotes the production of IL-17A by murine CD1d-driven invariant NKT cells in airway inflammation.

BACKGROUND: IL-17A is associated with different asthma phenotypes as virus-associated or steroid-resistant asthma. Invariant natural killer T (iNKT) cells play an important role in the pathogenesis of asthma. The aim of the study was to evaluate the activity of polyinosinic-polycytidylic acid [poly(I:C)] on IL-17A production by CD1d-activated iNKT cells. METHODS: We analysed the in vitro effect of poly(I:C) on the release of IL-17A by spleen and lung CD1d-activated iNKT cells with α-galactosylceramide (α-GalCer). Its activity was also investigated in an α-GalCer-induced murine models, including lung inflammation. The inhibition of IL-17A by Toll-like receptor (TLR) 7 agonists in the same in vitro and in vivo models has been analysed. RESULTS: Poly(I:C) upregulated the in vitro IL-17A production by CD1d-activated NK1.1- CD4- iNKT subset, without modifying type 1 and type 2 cytokines. The two stimuli selectively upregulated IL-17A serum levels in vivo. Their intratracheal administration resulted in increased airway hyper-reactivity (AHR), neutrophilia in bronchoalveolar lavage and airway inflammation, which were inhibited by anti-IL-17A antibody. Poly(I:C) effects were attributable to IL1ß and IL-23 release from dendritic cells, as showed by inhibition with neutralizing antibodies. TLR7 agonists inhibited the IL-17A production by poly(I:C) plus α-GalCer in the same models. Such effect was associated with the increased production by DC of IL-17A-inhibiting cytokines and the dampening of IL-1ß and IL-23. CONCLUSIONS: Synthetic dsRNA selectively expand a CD1d-driven IL-17A-producing iNKT cell subset, thus explaining the worsening of airway inflammation by some viral infections. TLR3- and TLR7-triggering viral sequences can exert variable and opposite effects on adaptive immune response.

Vav1 haploinsufficiency in a common variable immunodeficiency patient with defective T-cell function.

Common variable immunodeficiency (CVID) is a primary immune disorder characterized by impaired antibody production, which is in many instances secondary to defective T cell function (T-CVID). We previously identified a subset of T-CVID patients characterized by defective expression of Vav1, a guanine nucleotide exchanger which couples the T-cell antigen receptor to reorganization of the actin cytoskeleton. Here we have addressed the possibility that an intrinsic defect in the Vav1 gene might underlie the reduction in Vav protein observed in T cells from these patients. We report the identification in one T-CVID patient of a heterozygous deletion in Vav1. The gene deletion, spanning exons 2-27, accounts for the reduction in Vav1 mRNA and protein in T cells from this patient. The disease-related pedigree of this patient suggests a de novo origin of the Vav1 deletion. The findings highlights Vav1 as an autosomal dominant disease gene associated with CVID with defective T-cell function.

Anti-infliximab IgE and non-IgE antibodies and induction of infusion-related severe anaphylactic reactions.

BACKGROUND: Infliximab is a chimeric monoclonal antibody against TNF-alpha useful in the treatment of many chronic inflammatory diseases. Severe anaphylaxis has been reported during therapy, although the exact mechanism has not been fully defined. The reactions have been related to the infliximab immunogenicity and development of specific antibodies. AIMS OF THE STUDY: Evaluation of the development of IgE and non-IgE antibodies to infliximab and their relationship with infusion reaction. METHODS: Seventy-one patients (11 reactives, 11 therapeutically nonresponders, and 49 unreactive therapeutically responders) and 20 non-infliximab-exposed control subjects (ten rheumatoid arthritis, five spondyloarthropathies, five vasculitis) were evaluated for the presence of IgE (ImmunoCAP assay), IgM, and non-isotype-specific (ELISA assays) anti-infliximab antibodies. Sera were obtained at baseline and during the course of treatment, before each infliximab infusion. RESULTS: Eleven out of 71 patients had a hypersensitivity reaction to infliximab. Non-isotype-specific anti-infliximab antibodies were detected in eight reactive and two nonresponder patients. Three patients with severe reactions displayed anti-infliximab IgE antibodies and positive skin testing. Detectable levels of anti-infliximab IgM antibodies were shown in three additional IgE- and skin testing-negative patients. IgE and IgM antibodies to infliximab were not detectable in the two nonresponder patients. Antibodies developed before the 2nd and the 3rd infusion, and their appearance was strictly related to the timing of the reaction. CONCLUSIONS: This report indicates that in some patients with infliximab-related severe reactions, IgE or IgM antibodies against infliximab were detectable. The majority of reactions could be predicted by the appearance of anti-infliximab antibodies.

Influence of total serum IgE levels on the in vitro detection of beta-lactams-specific IgE antibodies.

BACKGROUND: Allergic reactions to beta-lactams are a frequent cause of adverse drug reactions; the diagnosis is based on history, clinical examination, skin testing (prick and intradermal) and demonstration of serum-specific IgE antibodies (Abs). OBJECTIVE: We compared the diagnostic performance of the Phadia CAP system for the detection of IgE to beta-lactams carried out using the new test with cut-off limits of 0.10 kUA/L and the old test with cut-off limits of 0.35 kUA/L for positive results; subsequently, we analysed the effect of total serum IgE values and of atopic phenotype on the diagnostic performance of the tests. METHODS: The study comprised a total of 34 patients with a history of immediate adverse reactions to beta-lactams, which were confirmed by positive skin testing, and 115 control subjects with tolerance to beta-lactams over the last year. The Phadia CAP System was used for the determination of serum total and specific IgE Abs towards penicilloyl G (c1), penicilloyl V (c2), ampicilloyl (c5) and amoxicilloyl (c6). The overall diagnostic performance was assessed as a diagnostic odds ratio (DOR). RESULTS: The new test showed a higher sensitivity (85% vs. 44%) than the old test and a lower specificity (54% vs. 80%) but the overall diagnostic performance was poor (DOR 6.78 vs. 3.16, P = 0.333) in both tests. The total IgE value influences the DOR of both tests; DOR was better for values under 200 kU/L [DOR = 66; 95% confidence interval (CI): 11.3-384.1] or 500 kU/L (DOR = 45.7; 95% CI: 5.3-394.4) for the new and old tests, respectively. CONCLUSIONS: The reduction in the positive cut off value has not significantly improved the overall diagnostic performance of the beta-lactams-specific IgE assay. Because of the influence of serum total IgE on the detection of beta-lactam-specific IgE Abs, the combination of both tests is mandatory in the in vitro diagnostic approach of beta-lactam allergy.

Safety and tolerability of infliximab therapy: suggestions and criticisms based on wide clinical experience.

Infliximab, an IgG1 monoclonal chimeric antibody against tumor necrosis factor (TNF)-alpha, represents the main biological drug employed for the treatment of several immuno-mediated inflammatory disorders. Infliximab infusion can be complicated by clinically heterogeneous adverse reactions, potentially interfering with the course of treatment. We analysed the adverse events recorded in 49 patients affected by different chronic inflammatory disorders (rheumatoid arthritis, seronegative spondyloarthritis, Behçet's disease, Wegener's granulomatosis, Churg-Strauss syndrome, Cogan's disease) who were receiving a total of 709 infliximab infusions, in order to correlate the development of infliximab reactions and their features to some potential risk factors. We displayed a lower frequency of infusion reactions (1.5 percent; 11 out of 709 infusions) than those previously reported. However, patients suffering from rheumatoid arthritis and/or patients who underwent re-treatment after a long period, showed a higher prevalence of infliximab-related reactions. In conclusion, in our experience infliximab treatment is rarely complicated by adverse reactions which are, more importantly, almost always mild. Some good clinical practices, such as the low rate of infusion, pre-treatment with anti-histamine and prednisone in all patients, chronic immunosuppressive therapy and avoidance of long intervals between infusions may represent a combined useful strategy to reduce the frequency of infliximab reactions and to increase safety.

Factors reducing omalizumab response in severe asthma.

BACKGROUND: Despite adding Omalizumab to conventional therapy, several severe asthmatics still show poor disease control. We investigated the factors that may affect a reduced Omalizumab response in a large population of severe asthmatics. METHODS: 340 patients were retrospectively evaluated. FEV1%, FVC%, Asthma Control Test (ACT), fractional exhaled nitric oxide (FENO), possible step-downs/step-ups of concomitant therapies, exacerbations, disease control levels, ICS doses and SABA use, observed at the end of treatment, were considered as a response to Omalizumab. RESULTS: Age was an independent risk factor for a reduced response concerning FEV1%, FVC%, ACT and for a lower asthma control. Obesity (vs normal weight) was a determinant condition for exacerbations (OR:3.114[1.509-6.424], p = 0.002), for a disease partial/no control (OR:2.665[1.064-6.680], p = 0.036), for excessive SABA use (OR:4.448[1.837-10.768], p = 0.002) and for an unchanged/increased level of concomitant asthma medications. Furthermore, obesity also reduced the response in FEV1 (ß = -6.981,p = 0.04), FVC (ß = -11.689,p = 0.014) and ACT (ß = -2.585, p = 0.027) and was associated with a higher FENO level (ß = 49.045,p = 0.040). Having at least one comorbidity was a risk factor for exacerbations (OR:1.383[1.128-1.697], p = 0.008) and for an ACT <20 (OR:2.410[1.071-3.690], p = 0.008). Specifically, chronic heart disease was associated with both a lower ACT and FVC% whereas gastroesophageal reflux with a partial/no asthma control. Nasal polyps were a predisposing factor leading both to exacerbations and to the use of higher inhaled corticosteroids doses. Moreover, smoking habits, pollen or dog/cat dander co-sensitizations may negatively influence Omalizumab response. CONCLUSION: Age, obesity, comorbidities, smoking habits, nasal polyps, allergic poly-sensitization might reduce Omalizumab effectiveness independently to other asthma-influencing factors.

Influence of impaired T- and B-cell compartments on efficacy of IVIg in dysimmune neuropathies.

Autoimmune mechanisms are postulated to play a role in the development and progression of dysimmune neuropathies (DN). We investigated the relation between lymphocyte number and marker expression, and disease activity in 20 patients with DN under intravenous immunoglobulins (IVIg) treatment. B- and T-lymphocyte markers were studied by flow cytometry of the expression of CD5, CD25, CD23 and CD38 markers on B cells and of CD3, CD4 and CD8 markers, respectively. These parameters were compared with those obtained from matched healthy volunteers. The proportions of CD38+ B cells were higher in patients compared with those of controls. Proportions of activated CD4+ and CD8+ T cells were comparable in peripheral blood mononuclear cells of patients and controls, but a significant reduction of the absolute numbers of CD3+, CD4+ and CD8+ cells were observed in DN patients. The percentages of CD25+ memory T cells were instead significantly increased in DN patients. Lastly, T-cell reduction and the CD19/CD38 ratio over total B (CD19+) cells directly correlated with a poor response to IVIg therapy. In DN, whereas T-cell number is reduced, activated T and B cells are increased, thus suggesting an intrinsic defect of the immune response.

Effects of omalizumab in severe asthmatics across ages: A real life Italian experience.

BACKGROUND: This retrospective study aimed at evaluating long-term effects of Omalizumab in elderly asthmatics in a real-life setting. METHODS: 105 consecutive severe asthmatics (GINA step 4-5; mean FEV1% predicted:66 ± 15.7) treated with Omalizumab for at least 1 year (treatment mean duration 35.1 ± 21.7 months) were divided into 3 groups according to their age at Omalizumab treatment onset: 18-39, 40-64 and ≥ 65 years. RESULTS: Comorbidities, number of overweight/obese subjects and patients with late-onset asthma were more frequent among older people. A similar reduction of inhaled corticosteroids dosage and SABA on-demand therapy was observed in all groups during Omalizumab treatment; a similar FEV1 increased was also observed. Asthma Control Test (ACT) improved significantly (p < 0.001) in the three groups, increasing from 15 [IQR:12-18] to 24 [IQR:22-25] in younger subjects, from 14 [IQR:10-16] to 21 [IQR:20-23] in the 40-64-year-group and from 15 [IQR:12-16] to 20 [IQR:18-22] in elderly patients where improvement was lower (p = 0.039) compared to younger people. Asthma exacerbations decreased significantly after Omalizumab but the percentage of exacerbation-free patients was higher in younger people (76.9%) compared to middle aged patients (49.2%) and the elderly (29%) (p = 0.049). After Omalizumab treatment, the risk for exacerbations was lower in subjects aged 40-64 (OR = 0.284 [CI95% = 0.098-0.826], p = 0.021) and 18-39 (OR = 0.133 [CI95% = 0.026-0.678], p = 0.015), compared to elderly asthmatics. Also, a significantly reduced ACT improvement (ß = -1.070; p = 0.046) passing from each age class was observed. CONCLUSION: Omalizumab improves all asthma outcomes independently of age, although the magnitude of the effects observed in the elderly seems to be lower than in the other age groups.

Defective production of LIF, M-CSF and Th2-type cytokines by T cells at fetomaternal interface is associated with pregnancy loss.

Development of CD4+ helper T (Th) cells into type 1 (Th1) or type 2 (Th2) effectors can be influenced by hormones enhanced during pregnancy. Progesterone, at concentrations comparable to those found at fetomaternal interface, promotes the production of IL-4 and IL-5, whereas relaxin promotes the production of IFN-gamma by T cells. Furthermore, Th1-type cytokines promote allograft rejection and, therefore, may compromise pregnancy, whereas Th2-type cytokines, which inhibit Th1 responses, may allow allograft tolerance. In addition, T cell production of Leukemia Inhibitory Factor (LIF) and macrophage-stimulating factor (M-CSF), which are essential for embryo implantation and development, are up-regulated by IL-4 and progesterone. Finally, a direct cause-and-effect relationship between the defective production of LIF, M-CSF and Th2-type cytokines by T cells present at feto maternal interface and the pregnancy loss has been observed.