Severe Opportunistic Infections Research Articles

Early Insights from Commercialization of Gene Therapies in Europe.

After years of research and development, gene therapies are now becoming a commercial reality with several products approved by European regulatory authorities [...].

CAUSES OF DEATH IN HIV-INFECTED PATIENTS IN A LARGE TUBERCULOSIS HOSPITAL OF KEMEROVO REGION

The aim was to study the causes of death in HIV patients in the Novokuznetsk tuberculosis dispensary in 2016 (population is 550 thousand people; about 2% of population are HIV-positive). Materials and methods: Protocols of all autopsies of HIV-infected patients (n=221) performed in 2016 in the Novokuznetsk tuberculosis dispensary. Results: The mean age of the deceased was 37 Ѓ }6,9 years. HIV and tuberculosis (TB) co-infection was in 83,3% of patients (n=184), HIV/TB and other opportunistic or severe somatic diseases – in 10,4% (n=23), non-tuberculous opportunistic diseases – in 6,3% (n=14). The new tuberculosis cases were in 71,1% (n=147), relapses – in 7,2% (n=15), chronic tuberculosis cases – in 21,7% of patients (n=45). Disseminated form prevailed among the cases of respiratory tuberculosis; generalized tuberculosis (3 and more localizations) occurred in 87,0% (n=180), tuberculosis meningitis was found in 17,9% (n=37). Positive fluorescent sputum microscopy was in 72.5%, sputum cultures on Loewenstein-Jensen medium – in 78,3% with HIV/TB. Primary multidrug resistance was detected in 60,7% (including in 5,8% of them with primary extensively drug resistance). Severe opportunistic infections or malignancies were in 9,2% of HIV/TB (n=19) and in 78,7% of non-TB patients (n=11). Data on the CD4 level was known in 68,8% of cases (n=152): the median count was 75,5 cells/ μ l; 38,9% of new TB cases (n=46) were diagnosed with HIV in time of TB detecting. Antiretroviral therapy was performed only 13% of patients (n=29). Conclusion: There is a need for the optimization of HIV detecting approaches and early initiation of antiretroviral therapy before the appearance of incurable opportunistic diseases, as well as for comprehensive TB prevention.

New Targeted Treatments for Cutaneous T-cell Lymphomas.

Cutaneous T-cell lymphomas (CTCLs) represent a group of rare and heterogeneous diseases that are very difficult to treat at advanced stages. The development of monoclonal antibodies is a new hope for the treatment of these diseases. Alemtuzumab (Campath) is a humanized IgG1 kappa monoclonal antibody specific for CD52, an antigen expressed by most T and B lymphocytes. Alemtuzumab may frequently induce long-term remissions in patients with Sezary syndrome but high-dose treatments lead to severe cytopenia, immune depletion, and opportunistic infections. This treatment is less efficient in mycosis fungoides (MF). Brentuximab vedotin is a chimeric anti-CD30 monoclonal antibody conjugated to monomethyl auristatin E, a cytotoxic antitubulin agent. Brentuximab vedotin is a very interesting new treatment for advanced tumor MF, Sezary syndrome, and primary cutaneous CD30+ lymphoproliferative disorders. The main limiting adverse event is neurosensitive peripheral neuropathy. Mogamulizumab is a humanized anti-C-C chemokine receptor Type 4 monoclonal antibody with a defucosylated Fc region leading to increased antibody-dependent cellular cytotoxicity. Mogamulizumab is very efficient on aggressive peripheral T-cell lymphomas, particularly adult T-cell leukemia/lymphoma and CTCLs, especially on the blood component of tumor cells. The main limiting events are related to the concomitant depletion of regulatory T-cells. IPH4102 is a humanized monoclonal antibody that targets the immune receptor KIR3DL2/CD158k. Preclinical results with this antibody offer proofs of concept for the clinical development of IPH4102 to treat patients with advanced CTCL.

Mukormykoza nosowo-mózgowa: obraz kliniczny, diagnostyka, leczenie – przegląd piśmiennictwa

Many pathogens present in the human environment, in immunocompromised patients, can cause extremely severe opportunistic infections. Most patients suffering from immunological disorders are rarely treated at maxillo-facial departments. In some special cases they require a direct clinical approach. Fungal infections in the cranio-facial area do not occur often, as opposed to infections from bacterial flora which are most frequently found. Some special conditions and requirements are needed to be present for the occurrence of fungal infections. If found, many of them are treated locally by antifungal medicaments, while a few of them require additional radical surgical excisional approach. Mucor sp. is one of these infections and it is related with mucormycosis (zygomycosis). Rhinocerebral zygomycosis is particularly dangerous. This rare cranio-facial infection is a great challenge for all clinicians and surgeons. It seems that only an accurate and proper diagnosis has an impact on the patient’s survival and post-treatment quality of life. In this paper we focus on recent clinical findings and treatment methods of this disease.

Prevalence of non-adherence to highly active antiretroviral therapy and its related clinical and therapeutic factors in Ouagadougou (Burkina Faso).

The study included 152 patients. Their mean age was 40.7±7.8 years, and the sex-ratio 0.3. The frequency of non-adherence to antiretroviral therapy was 38.2%. In the univariate analysis, laboratory and clinical factors associated with non-adherence were severe immune depression (P=0.03), opportunistic infections (P=0.001), and lack of clinical improvement (P=0.001), while the therapeutic factors associated with it were inadequate knowledge (P=0.001), side effects (P=0.003), and using the treatment secretly (P=0.001). In the multivariate analysis, opportunistic infections (OR=13.51, 95% CI 3.15-58.82, P=0.000), lack of clinical improvement (OR=4.16, 95% CI 1.06-16.32, P=0.04), inadequate knowledge (OR=16.12, 95% CI 1.67-166.66, P=0.01), and secret treatment use (OR=11.36, 95% CI 3.18-40.00, P=0.000) remained associated with non-adherence. The study underlines the need to improve strategies for the prescription of this therapy and for reinforcing patients' education and support.

Antimicrobial Activities of Different Parts of Calotropis gigantea: a Naturally Occurring Prophylactic Medicinal Shrub

The increased incidence of severe opportunistic fungal and bacterial infections is an important problem. Therefore, there is a great need in the determination of new classes of natural products that may be effective against bacteria and fungi. Plant extracts represent a continuous effort to find new compounds with the potential to act against multi resistant bacteria. The aim of this investigation was to carry out the analysis of antibacterial and antifungal activities of different parts of Calotropis gigantea. Antimicrobial activity of ethanol, methanol and chloroform extracts from flower, leaves and roots of C. gigantea, was examined against six species of pathogenic and non-pathogenic microorganisms: Escherichia coli, Bacillus subtilis, Klebsiella pneumonia, Staphylococcus aureus, Aspergillus niger and Candian albican using disc diffusion method. The maximum level of antibacterial activity was observed in flower extract against S. aureus (34 ± 0.43 mm) at the concentration of 20 mg of chloroform extract and there was less activity observed against A. niger (02 ± 0.10 mm) at the concentration of 5 mg of ethanol extract. The methanol extract of root showed highest antibacterial activity against S. aureus (28 ± 0.30 mm) at the concentration of 20 mg of extract, but less activity was observed in the chloroform extract against K. pneumonia (9 ± 0.01 mm). Methanol leaf extract of C. gigantea showed more active against K. pneumonia (12 ± 0.44 mm) at the concentration of 20 mg and less activity was observed in chloroform extract against E. coli. Hence, the isolation of antimicrobial compounds from flower, root and leaf of C. gigantea with possible mechanism would be a better option for the synthesis of new antimicrobial drugs to treat infectious diseases.

Étude rétrospective de la cryptococcose neuroméningée chez les patients infectés par le VIH dans le service des maladies infectieuses du CHU de Casablanca, Maroc

To report the cases of neuromeningeal cryptococcosis and to describe the clinical, paraclinical, therapeutic and outcomes of patients. Retrospective study of 43 patients infected with HIV admitted from January first 2010 to June 30th 2015 in the infectious disease unit of UHC Ibn Rochd, for neuromeningeal cryptococcus. The mean frequency of neuromeningeal cryptococcosis in patients infected with HIV was 1.4%. The mean age was 39 years and a sex ratio of 1.38. The mean CD4 count was 70 cells/mm3. The diagnosis of HIV was revealed by neuromeningeal cryptococcus in 77% of cases. Fifteen days interval was reported between the first symptom and hospital admission. Headache (77%) was the most represented clinical sign. The cerebrospinal fluid analysis showed hypoglycorachy (67%), hyperproteinorachy (65%) and lymphocytosis (63%). Chinese ink direct examination for Cryptococcus neoformans in CSF was positive in 86% of cases and all cases were positive after culture on Sabouraud's medium. Patients were treated with monotherapy amphotericin B (42%) or fluconazole (28%) and bitherapy amphotéricine B/fluconazole (28%). Fatal evolution was observed in 60% of cases. Neuromeningeal cryptococcosis remains a severe opportunistic infection in HIV patients with a heavy mortality rate.

Molecular epidemiology reveals genetic diversity among 363 isolates of the Cryptococcus neoformans and Cryptococcus gattii species complex in 61 Ivorian HIV-positive patients.

Cryptococcal meningitis is a severe opportunistic infection in HIV-infected patients. In Ivory Coast, despite the availability of antiretroviral treatment (ART), this infection is still prevalent. The study investigates the genetic diversity of 363 clinical isolates of Cryptococcus from 61 Ivorian HIV-positive patients, the occurrence of mixed infections and the in vitro antifungal susceptibility of the isolates. Serotyping was performed via LAC1 and CAP64 gene amplification. Genotyping was performed using the phage M13 core (GACA)4 and (GTG)5 primers and restriction fragment length polymorphism analysis of the URA5 gene. By PCR fingerprinting, the presence of the three serotypes were demonstrated among the 363 isolates in the population studied: A (n=318; 87.6%), AD (n=40; 11%) and B (n=4; 1.1%). Using PCR fingerprinting with primers M13 (GACA)4 and (GTG)5 , we grouped the isolates into 56 molecular subtypes. We observed a high frequency (39.3%) of mixed infections, with up to two different genotypes per sample. None of the isolates were resistant to amphotericin B. Only 0.3% and 1.1% of the isolates were resistant to fluconazole and flucytosine respectively. This study revealed the high genetic diversity among Cryptococcus isolates, the occurrence of mixed infections and a high antifungal susceptibility for the majority of Ivorian cryptococcal isolates.

The Impact of Azathioprine-Associated Lymphopenia on the Onset of Opportunistic Infections in Patients with Inflammatory Bowel Disease

BackgroundThiopurines are known to cause lymphopenia (<1,500 lymphocytes/μl). As severe lymphopenia (<500C/μl) is associated with opportunistic infections, we investigated severity of thiopurine-related lymphopenia and development of opportunistic infections in our tertiary referral centre.MethodsWe retrospectively screened medical records of 1,070 IBD patients and identified 100 individuals that developed a total of 161 episodes of lymphopenia during thiopurine treatment between 2002 and 2014. Occurrence of opportunistic infections was documented. A control group consisted of IBD patients receiving thiopurines but without developing lymphopenia.ResultsOf a total of 161 episodes of lymphopenia, 23% were severe (<500C/μl). In this subgroup, thiopurine dosing was modified in 64% (dosage reduction: 32%, medication discontinued: 32%). We identified 9 cases (5.5%) of opportunistic infections, of which only two occurred during severe lymphopenia. One opportunistic infection (4.5%) was identified in the control group. No association was found between opportunistic infections and severity of lymphopenia. All patients who suffered from opportunistic infections were receiving additional immunosuppressive medication.ConclusionOur patients treated with thiopurines rarely developed severe lymphopenia and opportunistic infections did not occur more often than in the control group. A careful monitoring of lymphocytes and prophylactic adjustment of thiopurine therapy might contribute to this low incidence.

DYNAMICS OF CLINICAL LABORATORY PARAMETER IN HIV-INFECTED CHILDREN UNDERGOING DIFFERENT PATTERNS OF INITIAL HIGHLY ACTIVE ANTIRETROVIRAL THERAPY: RANDOMIZED CONTROLLED TRIAL

Background: Adverse course of HIV infection, rapid development of immunosuppression, severe opportunistic infections and malignant tumors and high mortality substantiate the importance of timely prescription of highly active antiretroviral therapy (HAART). The initial therapy pattern must remain efficient and safe in the long term. Objective: Our aim was to study effectiveness and safety of different patterns of initial HAART in HIV-infected children. Methods: The randomized controlled trial involved HIV-infected children aged 1–3 years. Clinical, immunological and virological examinations were conducted before and 12 months after HAART. The initial therapy pattern included 2 nucleoside HIV reverse transcriptase inhibitors — zidovudine and lamivudine. Children were randomized to the groups differing in the third therapy component: lopinavir/ritonavir or nevirapine. Results: 25 patients were randomized to the lopinavir/ritonavir group, 23 children — to the nevirapine group. After 12 months of treatment, HIV replication suppression (blood viral load < 50 copies/ml) was achieved in 25 (100%) lopinavir/ritonavir group patients and in 16 (70%) nevirapine group patients (p = 0.003). HIV infection did not progress clinically regardless of the pattern. The median number of CD4+CD3+ lymphocytes in the lopinavir/ritonavir group increased from 20.5% (12; 23) to 30% (27; 34) (p < 0,001), in the nevirapine group — from 21.5% (17; 23) to 29% (27; 38) (p < 0.001). Adverse events developed in 13 (27%) children. 3 and 2 children in the lopinavir/ritonavir group suffered from nausea and emesis, respectively. 1 and 1 patient in the nevirapine group suffered from allergic rash and drug-induced hepatitis, respectively. Conclusion: High effectiveness and safety of lopinavir/ritonavir allow recommending this drug as the third component of the initial HAART pattern for HIV-infected children.

Long-Term Follow-Up of the Edmonton Protocol of Islet Transplantation in the United States

We report the long-term follow-up of the efficacy and safety of islet transplantation in seven type 1 diabetic subjects from the United States enrolled in the multicenter international Edmonton Protocol who had persistent islet function after completion of the Edmonton Protocol. Subjects were followed up to 12 years with serial testing for sustained islet allograft function as measured by C-peptide. All seven subjects demonstrated continued islet function longer than a decade from the time of first islet transplantation. One subject remained insulin independent without the need for diabetic medications or supplemental transplants. One subject who was insulin-independent for over 8 years experienced graft failure 10.9 years after the first islet transplant. The remaining six subjects demonstrated continued islet function upon trial completion, although three had received a supplemental islet transplant each. At trial completion, five subjects were receiving insulin and two remained insulin independent, although one was treated with liraglutide. The median hemoglobin A1c was 6.3% (45 mmol/mol). All subjects experienced progressive decline in the C-peptide/glucose ratio. No patients experienced severe hypoglycemia, opportunistic infection, or lymphoma. Thus, although the rate and duration of insulin independence was low, the Edmonton Protocol was safe in the long term. Alternative approaches to islet transplantation are under investigation.

Pneumocystis pneumonia outbreak among renal transplant recipients at a North American transplant center: Risk factors and implications for infection control

Pneumocystis pneumonia is a severe opportunistic fungal infection. Outbreaks among renal transplant recipients have been reported in Europe and Japan, but never in North America. We conducted a retrospective case-control study among adult renal transplant recipients at a Canadian center, using a 3:1 matching scheme. Ten cases and 30 controls were matched based on initial transplantation date, and all patients received prophylaxis with trimethoprim-sulfamethoxazole for 1 year posttransplantation. The median time between transplantation and infection was 10.2 years, and all patients survived. Compared with controls, case patients had statistically lower estimated glomerular filtration rate (29.3 mL/min vs 66.3 mL/min; P = .028) and lymphopenia (0.51 × 10(9)/L vs 1.25 × 10(9)/L; P = .002). Transmission mapping revealed significant overlap in the clinic and laboratory visits among case vs control patients (P = .0002). One hundred percent of patients (4 out of 4) successfully genotyped had the same strain of Pneumocystis jirovecii. Our study demonstrated an outbreak of pneumocystis more than 10 years following initial transplantation, despite using recommended initial prophylaxis. We identified low estimated glomerular filtration rate and lymphopenia as risk factors for infection. Overlapping ambulatory care visits were identified as important potential sources of infection transmission, suggesting that institutions should re-evaluate policy and infrastructure strategies to interrupt transmission of respiratory pathogens.

Pulmonary toxoplasmosis in human immunodeficiency virus-infected patients in the era of antiretroviral therapy.

Toxoplasmosis is a severe opportunistic infection in patients infected with the human immunodeficiency virus (HIV). The lung is a major site of infection after the central nervous system. In this report we described two cases of pneumonia due to Toxoplasma gondii infection in HIV patients with antiretroviral therapy. Clinical and radiological abnormalities are not specific. Pulmonary toxoplasmosis should be considered in HIV-infected patients with late stage of HIV, CD4 count less than 100 cells/µl and a poor adherence to HAART.

Toxoplasmosis in HIV infection: An overview.

Toxoplasma gondii is an obligate intracellular protozoan parasite presenting as a zoonotic infection distributed worldwide. In HIV-positive individuals, it causes severe opportunistic infections, which is of major public health concern as it results in physical and psychological disabilities. In healthy immunocompetent individuals, it causes asymptomatic chronic persistent infections, but in immunosuppressed patients, there is reactivation of the parasite if the CD4 counts fall below 200 cells/μl. The seroprevalence rates are variable in different geographic areas. The tissue cyst or oocyst is the infective form which enters by ingestion of contaminated meat and transform into tachyzoites and disseminate into blood stream. In immunocompetent persons due to cell-mediated immunity the parasite is transformed into tissue cyst resulting in life long chronic infection. In HIV-infected people opportunistic infection by T. gondii occurs due to depletion of CD4 cells, decreased production of cytokines and interferon gamma and impaired cytotoxic T-lymphocyte activity resulting in reactivation of latent infection. The diagnosis can be done by clinical, serological, radiological, histological or molecular methods, or by the combination of these. There is various treatment regimen including acute treatment, maintenance therapy should be given as the current anti T. gondii therapy cannot eradicate tissue cysts. In HIV patients, CD4 counts <100; cotrimoxazole, alternately dapsone + pyrimethamine can be given for 6 months. Hence, early diagnosis of T. gondii antibodies is important in all HIV-positive individuals to prevent complications of cerebral toxoplasmosis.

A Rare Case of Juvenile Systemic Lupus Erythematosus with Disseminated Histoplasmosis.

Histoplasmosis is a systemic fungal infection caused by dimorphic fungus, Histoplasma capsulatum. Immunocompetent individuals usually have self-limiting or localized disease whereas immunocompromised individuals develop disseminated disease. The occurrence of progressive disseminated histoplasmosis in juvenile systemic lupus erythematosus is extremely rare with only one reported case in literature showing such association. Therefore, we report a case of severe opportunistic fungal infection caused by Histoplasma in a 13-year-old girl who was diagnosed with juvenile lupus erythematosus, subsequently developed septic shock and died of the disease despite of aggressive antifungal therapy.

Cytomegalovirus-Associated Gastroduodenal Ulcers in a Patient With Functional Hypercortisolism

Cytomegalovirus (CMV)-associated gastroduodenal ulcers (GDU) are a rare digestive disease, which principally affect immunocompromised patients. We recently experienced CMV-associated GDU occurring in a seemingly immunocompetent patient. The rarity of such a condition was inimical to a correct clinical diagnosis.A 77-year-old woman with Alzheimer's disease was admitted to our hospital because of vomiting and anorexia. Her general condition was extremely poor due to severe dehydration. Any invasive procedures including gastroduodenal endoscopy could not be performed. Laboratory test results showed electrolyte imbalance, hyperglycemia, and hypercortisolemia. The plasma adrenocorticotropic hormone level was rather low. On her 11th day in hospital, she suddenly fell into shock status. Despite intensive care, the patient could not be rescued. An autopsy was performed and revealed that she had suffered from CMV-associated GDU and died of candidemia that invaded through the ulcer. Her adrenal glands showed neither neoplasm nor hyperplasia, suggesting that her hypercortisolism was a purely functional disorder. We concluded that the severe opportunistic infections were developed in association with functional hypercortisolism.This case suggests that functional hypercortisolism, even though transient, can cause a patient to be immunocompromised.

A novel multiple locus variable number of tandem repeat (VNTR) analysis (MLVA) method for Propionibacterium acnes

Propionibacterium acnes plays a central role in the pathogenesis of acne and is responsible for severe opportunistic infections. Numerous typing schemes have been developed that allow the identification of phylotypes, but they are often insufficient to differentiate subtypes. To better understand the genetic diversity of this species and to perform epidemiological analyses, high throughput discriminant genotyping techniques are needed. Here we describe the development of a multiple locus variable number of tandem repeats (VNTR) analysis (MLVA) method. Thirteen VNTRs were identified in the genome of P. acnes and were used to genotype a collection of clinical isolates. In addition, publically available sequencing data for 102 genomes were analyzed in silico, providing an MLVA genotype. The clustering of MLVA data was in perfect congruence with whole genome based clustering. Analysis of the clustered regularly interspaced short palindromic repeat (CRISPR) element uncovered new spacers, a supplementary source of genotypic information. The present MLVA13 scheme and associated internet database represents a first line genotyping assay to investigate large number of isolates. Particular strains may then be submitted to full genome sequencing in order to better analyze their pathogenic potential.

New Short Tandem Repeat-Based Molecular Typing Method for Pneumocystis jirovecii Reveals Intrahospital Transmission between Patients from Different Wards.

Pneumocystis pneumonia is a severe opportunistic infection in immunocompromised patients caused by the unusual fungus Pneumocystis jirovecii. Transmission is airborne, with both immunocompromised and immunocompetent individuals acting as a reservoir for the fungus. Numerous reports of outbreaks in renal transplant units demonstrate the need for valid genotyping methods to detect transmission of a given genotype. Here, we developed a short tandem repeat (STR)-based molecular typing method for P. jirovecii. We analyzed the P. jirovecii genome and selected six genomic STR markers located on different contigs of the genome. We then tested these markers in 106 P. jirovecii PCR-positive respiratory samples collected between October 2010 and November 2013 from 91 patients with various underlying medical conditions. Unique (one allele per marker) and multiple (more than one allele per marker) genotypes were observed in 34 (32%) and 72 (68%) samples, respectively. A genotype could be assigned to 55 samples (54 patients) and 61 different genotypes were identified in total with a discriminatory power of 0.992. Analysis of the allelic distribution of the six markers and minimum spanning tree analysis of the 61 genotypes identified a specific genotype (Gt21) in our hospital, which may have been transmitted between 10 patients including six renal transplant recipients. Our STR-based molecular typing method is a quick, cheap and reliable approach to genotype Pneumocystis jirovecii in hospital settings and is sensitive enough to detect minor genotypes, thus enabling the study of the transmission and pathophysiology of Pneumocystis pneumonia.

Initial suboptimal CD4 reconstitution with antiretroviral therapy despite full viral suppression in a cohort of HIV-infected patients in Senegal

ObjectiveWe determined the risk factors and incidence of clinical events associated with suboptimal immune reconstitution (SIR) defined by an increase in CD4 inferior to 50cells/μL, from inclusion up to six months of antiretroviral treatment (ARVT), in patients with an undetectable viral load (<50copies/mL). MethodsLogistic regression and Cox's proportional hazards model were used to examine risk factors for SIR and the association between SIR and the risk of new clinical events or death, respectively after six months of ARVT. ResultsOne hundred and two (15.5%) of the 657 patients presented with SIR. Age>40years (aOR=1.74, 95% CI=1.10–2.75), baseline CD4≥100cells/μL (aOR=2.06, 95% CI=1.24–3.42), ARVT including AZT (aOR=4.57, 95% CI=1.06–19.76), and the occurrence of a severe opportunistic infection during the first semester of ARVT (aOR=2.38 95% CI=1.49–3.80) were associated with SIR. After six months of ARVT and up to seven years of follow-up, 39 patients with SIR had presented with an opportunistic infection or death (rate=9.78/100 person-years) compared to 168 with a normal recovery (rate=7.75/100 person-years) but the difference was not statistically significant (aHR=1.22, 95% CI=0.85 to 1.74). ConclusionSIR is less common in our country and is not associated with increased mortality or a greater incidence of opportunistic infections after six months of ARVT.

DUSP4-mediated accelerated T-cell senescence in idiopathic CD4 lymphopenia

AbstractIdiopathic CD4 lymphopenia (ICL) is a rare heterogeneous immunological syndrome of unclear etiology. ICL predisposes patients to severe opportunistic infections and frequently leads to poor vaccination effectiveness. Chronic immune activation, expansion of memory T cells, and impaired T-cell receptor (TCR) signaling have been reported in ICL, but the mechanistic and causative links remain unclear. We show that late-differentiated T cells in 20 patients with ICL displayed defective TCR responses and aging markers similar to those found in T cells from elderly subjects. Intrinsic T-cell defects were caused by increased expression of dual-specific phosphatase 4 (DUSP4). Normalization of DUSP4 expression using a specific siRNA improved CD4+ T-cell activity in ICL, as this restored TCR-induced extracellular signal-regulated kinase activation and increased the expression of the costimulatory molecules CD27 and CD40L. Conversely, repeated TCR stimulation led to defective signaling and DUSP4 overexpression in control CD4+ T cells. This was associated with gradual acquisition of a memory phenotype and was curtailed by DUSP4 silencing. These findings identify a premature T-cell senescence in ICL that might be caused by chronic T-cell activation and a consequential DUSP4-dependent dampening of TCR signaling.