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Background Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has a variable clinical course with significant mortality. Early reports suggested higher rates of SARS‐CoV‐2 infection in patients with type A blood and enrichment of type A individuals among COVID‐19 mortalities. Study Design and Methods The study includes all patients hospitalized or with an emergency department (ED) visit who were tested for SARS‐CoV‐2 between March 10, 2020 and June 8, 2020 and had a positive test result by nucleic acid test (NAT) performed on a nasopharyngeal swab specimen. A total of 4968 patients met the study inclusion criteria, with a subsequent 23.1% (n = 1146/4968) all‐cause mortality rate in the study cohort. To estimate overall risk by ABO type and account for the competing risks of in‐hospital mortality and discharge, we calculated the cumulative incidence function (CIF) for each event. Cause‐specific hazard ratios (csHRs) for in‐hospital mortality and discharge were analyzed using multivariable Cox proportional hazards models. Results Type A blood was associated with the increased cause‐specific hazard of death among COVID‐19 patients compared to type O (HR = 1.17, 1.02–1.33, p = .02) and type B (HR = 1.32,1.10–1.58, p = .003). Conclusions Our study shows that ABO histo‐blood group type is associated with the risk of in‐hospital death in COVID‐19 patients, warranting additional inquiry. Elucidating the mechanism behind this association may reveal insights into the susceptibility and/or immunity to SARS‐CoV‐2.

The severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has led to a major pandemic. While vaccine development moves forward, optimal treatment continues to be explored. Efforts include an ever‐expanding number of clinical trials along with newly proposed experimental and off‐label investigational therapies; one of which is therapeutic plasma exchange (TPE). There have been a number of publications on TPE use as adjunctive therapy for coronavirus disease 2019 (COVID‐19), but no prospective randomized controlled trials (RCTs) have been completed. This article critically appraises the current available evidence on TPE as a treatment modality for SARS‐CoV‐2 infection.

Background: Autologous hematopoietic stem cell transplant (auto-HSCT) is a commonly used treatment for multiple myeloma (MM) and for relapsed/refractory non-Hodgkin lymphomas (NHL) for patients who are 65 years old, and nearly half of those are in patients >75 years old. While some studies have evaluated the use of auto-HSCT in older patients 65-75 years of age, there are few studies evaluating the relative safety of this treatment in patients above the age of 75 years. Such patients and their providers require outcome data of auto-HSCT in the elderly in order to help guide informed decision-making. Methods: We conducted a retrospective cohort study comparing short-term outcomes for auto-HSCT in patients >75 years old and 55-65 years old for the diagnosis of MM or NHL, who were conditioned with either melphalan or BEAM (carmustine, etoposide, cytarabine, melphalan) respectively. To identify patients, we used an internal database of auto-HSCT performed between 2005 - 2021. The study group included patients >75 years old. The control group included patients 55-65 years old that were matched to the study group patients by sex and time of transplant. Medical records were reviewed to gather data on demographics, pre-transplant functional status, transplant indication and conditioning regimen, length of stay, admission mortality, 30-day rehospitalization rate, ICU admission, neutropenic fever and infectious workup results, and time to WBC and platelet engraftment. The primary outcomes of the study were admission mortality, length of stay, time to WBC and platelet engraftment incidence, incidence of neutropenic fever, positive blood culture, ICU admission, and 30-day rehospitalization rate. Averages were calculated using medians and IQR. Admission mortality was evaluated using log rank test. P values were calculated using Fisher's test for categorical data and Wilcoxon rank sum test for continuous data. Significance was denoted by α =0.05. Results: We identified 43 patients aged >75 years old who underwent autologous stem cell transplant for multiple myeloma or lymphoma with melphalan or BEAM conditioning at Montefiore Medical Center between 2005-2021. Patient characteristics (Table 1) The earliest transplant in out cohort was in 12/2005 and the latest was in 3/2021. The median time between transplants of patients in the study and cohort groups was 14 [7.5, 24] days. 24 (55.8%) patients were female. The median age in the study group was 77.1 [76.2, 77.9] years old and 61.9 [57.4, 63.0] years old in the control group. Both groups predominantly included patients from minority populations: 55.8 and 46.5% were Spanish/Hispanic/Latino and 25.6% and 14.0% were African American, in study and control groups respectively. Multiple myeloma was the most common indication for auto-HSCT. Primary outcomes (Table 2) Admission mortality did not differ significantly between the groups, with only one death in the control group (p = 0.083). The length of stay was comparable at 18 [17, 22] days and 19 [16, 20] days (p = 0.2) for study and control groups, respectively. Time to WBC engraftment in the study group was 12 [11, 12] days and 11 [11, 12] days in the control group (p = 0.032). Time to platelet engraftment in the study group was 14 [12, 15] days and 12 [11, 14] days in the control group (p = 0.014). Although both time to WBC and platelet engraftment was significantly longer in the study group, the clinical significance of this finding is questionable, especially as it did not seem to prolong length of stay. There was no significant difference between incidence of neutropenic fever, or between incidence of positive blood cultures in patients with neutropenic fever. There was a non-statistically significant increase in the rate of ICU admissions in the study group vs control group 4/43 and 0/43 respectively (p=0.12). 30-day rehospitalization rate was comparable between the two groups. Conclusion: We did not find a statistically significant increase in morbidity or mortality for patients 75-80 years of age undergoing auto-HSCT compared with patients 55-65 years old. To our knowledge this is the largest cohort to date demonstrating the safety of auto-HSCT in this elderly population. Figure 1 Figure 1. Disclosures Gritsman: iOnctura: Research Funding. Shastri: Onclive: Honoraria; GLC: Consultancy; Kymera Therapeutics: Research Funding; Guidepoint: Consultancy. Verma: Medpacto: Research Funding; Curis: Research Funding; Eli Lilly: Research Funding; Stelexis: Consultancy, Current equity holder in publicly-traded company; Novartis: Consultancy; Acceleron: Consultancy; Celgene: Consultancy; Stelexis: Current equity holder in publicly-traded company; Throws Exception: Current equity holder in publicly-traded company; Incyte: Research Funding; GSK: Research Funding; BMS: Research Funding.

BACKGROUND: Adoptive immunotherapy using CD19-targeted Chimeric antigen receptor T cells (CAR-T) has revolutionized the treatment of relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Data is limited on the propensity of infections and lymphohematopoietic reconstitution after Day 30 (D30) following CAR-T cell therapy. In this study, we evaluated the prevalence and nature of infectious complications in an expanded cohort of DLBCL patients treated with CD19 CAR-T therapy and its association with the dynamics of leukocyte subpopulation reconstitution post-CAR-T cell therapy. METHODS: We conducted a retrospective study including 19 patients who received axicabtagene ciloleucel and investigated associations between cytopenia and infectious complications after D30. RESULTS: Nineteen patients were included, consisting of 42% Hispanic, 32% Caucasian, 21% African-American, and 5% Asian subjects. Post-D30 of CAR-T infusion, 47% patients (n=9) developed an infection and 53% (n=10) remained infection-free. The most common infection type observed was viral (7 patients) followed by bacterial (5 patients) and fungal (3 patients). Of 25 total infectious events, 56% were grade 1 or 2 and 44% were grade 3 with 10 being viral in etiology. To determine the kinetics of lymphohematopoietic reconstitution and its association with infection risk, we evaluated the relationship between cytopenias and rates of infection after D30. Notably, compared to non-infection group, infection group had a higher median absolute lymphocyte count (ALC) (1,000/µL vs. 600/µL, P1,500/µL in the infection group as opposed to 70% in the non-infection group at D90 (P

Background: Adoptive immunotherapy using CD19-targeted Chimeric Antigen Receptor T-cells (CAR-T) has revolutionized the treatment of relapsed/refractory diffuse large B-cell lymphoma (DLBCL). We have demonstrated the efficacy of FDA-approved axicabtagene ciloleucel (Yescarta) in a multiethnic New York City underserved population with 80% complete response (CR) rate in the first ten patients treated at our institution (Abbasi et al., 2020). There is limited data on the propensity of infections and lymphohematopoietic reconstitution after Day 30 (D30) following CAR-T cell therapy. In this study, we evaluated the prevalence and nature of infectious complications in an expanded cohort of DLBCL patients treated with CD19 CAR-T therapy and its association with the dynamics of leukocyte subpopulation reconstitution post-CAR-T cell therapy. Methods: We conducted a retrospective study of patients who received CAR-T therapy at our institution between 2018-2020. Variables collected include patient demographics, absolute neutrophil (ANC), lymphocyte (ALC) and monocyte counts (AMC) at Day 30, hematologic reconstitution (ANC≥ 1500/µL) at Day 90 (D90), presence or absence of infections after D30 by clinical and/or microbiological parameters. Associations between presence of infection and D30 ANC, ALC, AMC, ANC/ALC ratio, AMC/ALC ratio were assessed using Kruskal-Wallis test. Association between infection and hematologic reconstitution at D90 was done using Chi-square test. Kaplan-Meier curves with log-rank test were used to evaluate overall survival (OS) and progression-free survival (PFS). Results: Nineteen patients were evaluated in our study, consisting of 42% (8) Hispanic, 32% (6) Caucasian, 21% (4) African-American, and 5% (1) Asian subjects. Based on clinical and microbiologic data, 47% (9) developed an infection after D30 (infection group) while 53% (10) of subjects remained infection-free after D30 (non-infection group). The most common infection type observed was viral (11 patients) followed by bacterial (8 patients) and fungal (3 patients) (Table 1). Of 25 total infectious events, 44% (11) were grade 1 or 2 and 48% (12) were grade 3 with 10 being viral in etiology. Two deaths occurred due to an infectious process. Three patients tested SARS-CoV-2 positive and were hospitalized with COVID-19 pneumonia. Median OS and PFS has not been reached in either group. To determine the kinetics of lymphohematopoietic reconstitution and its association with infection risk, we evaluated the relationship between cytopenias and rates of infection after D30. Notably, compared to non-infection group, infection group had a higher median ALC (1000/µL vs 600/µL p=0.04), a lower median ANC/ALC ratio (1.4 vs 4.5 p1500/µL) at D90. We observed that only 22% (2) of patients had recovered ANC > 1500/µLin the infection group as opposed to 80% (8) in the non-infection group at D90 (p= 0.038). Rates of cytokine release syndrome (CRS) were comparable between the two groups (55.6% vs 70% p=0.52). Surprisingly, rates of immune-effector cell associated neurotoxicity syndrome (ICANS) was lower (55.6%) in the infection group compared to (90%) non-infection group (p=0.09). Fourteen of 19 patients had follow-up over one year, of which 8 (57%) remained in complete remission (CR). Conclusions: We demonstrate an infection rate of 47% (9) beyond D30 in patients undergoing CD19 CAR-T. Increased ALC, lower ANC/ALC and AMC/ALC ratios at D30 may be predictive of infectious complications. Median OS has not been reached in our cohort. Given the potential clinical impact, our observations should be corroborated using larger datasets. Disclosures Steidl: Pieris Pharmaceuticals: Consultancy; Bayer Healthcare: Research Funding; Stelexis Therapeutics: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Aileron Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Janakiram:ADC Therapeutics, FATE therapeutics, TAKEDA pharmaceuticals: Research Funding. Verma:BMS: Consultancy, Research Funding; acceleron: Consultancy, Honoraria; Janssen: Research Funding; stelexis: Current equity holder in private company; Medpacto: Research Funding.

Background Sickle Cell Disease (SCD) is an autosomal recessive disorder, which results from a point mutation in the β-globin gene. The production of mutant Hb S (V6E) leads to hemolytic anemia and numerous clinical complications. Patients homozygous for HbS gene (SS) typically rely on life-long transfusion therapy. Alloimmunization to foreign RBC antigens in multiply transfused patients is significantly more frequent in SS patients (observed in 7–47%) compared to patients with HbA (AA), and can pose a significant hurdle in finding compatible RBCs. However, the mechanism for enhanced alloimmunization in SS patients has not yet been elucidated. Patients heterozygous for HbS (SA) have a no distinct clinical phenotype and do not typically require transfusions. We investigated the rate of RBC antigen alloimmunization and specificity in SA patients. Aim The aim of this study was to determine and compare the rate and specificities of RBC antigen pregnancy-related alloimmunization in SA and AA patients. Methods In our retrospective study, we identified females who delivered a newborn between January 2014 to October 2019, for whom prenatal hemoglobin electrophoresis testing, and prenatal and perinatal antibody screening and identification was performed. R (V.3.6.2) statistical computing program was used for analysis. Results A total of 41735 subjects were identified: 40058 (AA) and 1677 (SA). African Americans were more prevalent in the SA compared to the AA group (55.8% vs 29.4%, P The most common antibody identified was anti-E (SA 42% vs AA 28%), anti-Lea (SA 21% vs AA 13%) and anti-C (SA 5% vs AA 12%). Subjects with pre-existing alloantibodies had a 5.4x increased risk of forming a new allo-antibody. However only 0.1% of subjects had a history of prior allo-antibodies, with no significant difference identified between AA and SA. Conclusions SA patients were found to have an increased rate of pregnancy-related alloimmunization (OR 1.75, P=0.02) after adjusting for the effects of increasing age, RH type, ethnicity, number of previously existing antibodies and number of transfusions in pregnancy.

I - uptake in the thyroid, the first step in thyroid hormone biosynthesis, is mediated by the Na + /I - symporter (NIS) with an electrogenic 2Na + : 1I - stoichiometry. We have obtained mechanistic information on NIS by characterizing the congenital I - transport defect-causing NIS mutant G93R. This mutant is targeted to the plasma membrane but is inactive. Substitutions at position 93 show that the longer the side chain of the neutral residue at this position, the higher the K m for the anion substrates. Unlike WT NIS, which mediates symport of Na + and the environmental pollutant perchlorate electroneutrally, G93T/N/Q/E/D NIS, strikingly, do it electrogenically with a 2∶1 stoichiometry. Furthermore, G93E/Q NIS discriminate between anion substrates, a discovery with potential clinical relevance. A 3D homology model of NIS based on the structure of the bacterial Na + /galactose transporter identifies G93 as a critical player in the mechanism of the transporter: the changes from an outwardly to an inwardly open conformation during the transport cycle use G93 as a pivot.

Thyroid dysfunction is a global health concern, causing defects including neurodevelopmental disorders, dwarfism and cardiac arrhythmia. Here, we show that the potassium channel subunits KCNQ1 and KCNE2 form a thyroid-stimulating hormone-stimulated, constitutively active, thyrocyte K+ channel required for normal thyroid hormone biosynthesis. Targeted disruption of Kcne2 in mice impaired thyroid iodide accumulation up to eightfold, impaired maternal milk ejection, halved milk tetraiodothyronine (T4) content and halved litter size. Kcne2-deficient mice had hypothyroidism, dwarfism, alopecia, goiter and cardiac abnormalities including hypertrophy, fibrosis, and reduced fractional shortening. The alopecia, dwarfism and cardiac abnormalities were alleviated by triiodothyronine (T3) and T4 administration to pups, by supplementing dams with T(4) before and after they gave birth or by feeding the pups exclusively from Kcne2+/+ dams; conversely, these symptoms were elicited in Kcne2+/+ pups by feeding exclusively from Kcne2-/- dams. These data provide a new potential therapeutic target for thyroid disorders and raise the possibility of an endocrine component to previously identified KCNE2- and KCNQ1-linked human cardiac arrhythmias.

We aimed to determine incidence, pathologic findings, prognostic factors and clinical outcomes for patients with clinically localized papillary RCC. Demographic, clinical and pathologic findings were collected on all patients with PRCC undergoing surgery at four academic medical centers. The primary endpoint was cancer-specific survival (CSS). Relapse-free survival (RFS) and overall survival (OS) were secondary endpoints. Kaplan–Meier estimates were obtained, and Cox proportional hazard regression models were used to assess predictors of mortality and relapse. We identified 626 PRCC, of which 373 (60 %) were type 1 and 253 (40 %) were type 2, with three-quarters of all tumors being pT1. Compared to patients with type 1, those with type 2 were older (mean age: 63 vs 61; p = 0.02), presented more commonly with symptoms (13 vs 7 %; p = 0.02) and had larger mean tumor size (5.2 vs 4.3 cm; p = 0.001). With a median follow-up of 41 months (IQR: 16–68), 92 patients had died of PRCC (15 %), 48 (8 %) experienced relapse, and 101 died from all causes (16 %). The estimated 5-year CSS, RFS and OS were 83, 91 and 82 %, respectively. In multivariable analysis, older age, T stage and nodal status were predictors of CSS and OS. However, PRCC subtype was not a predictor of CSS, RFS or OS. While patients with type 2 PRCC appear to present with more advanced disease than patients with type 1, PRCC subtype does not appear to be an independent predictor of CSS, RFS or OS for treated localized disease.

We report an extensive characterization of the Na + /monocarboxylate transporter (SMCT), a plasma membrane protein that mediates active transport of monocarboxylates such as propionate and nicotinate, and we show that SMCT may play a role in colorectal cancer diagnosis. SMCT, the product of the SLC5A8 gene, is 70% similar to the Na + /I − symporter, the protein that mediates active I − uptake in the basolateral surface of thyrocytes and other cells. SMCT was reported in the apical surface of thyrocytes and formerly proposed also to transport I − and was called the apical I − transporter. However, it is now clear that SMCT does not transport I − . Here we demonstrate a high-affinity Na + -dependent monocarboxylate transport system in thyroid cells, which is likely to be SMCT. We show that, whereas thyroidal Na + /I − symporter expression is thyroid-stimulating hormone (TSH)-dependent and basolateral, SMCT expression is TSH-independent and apical not only in the thyroid but also in kidney and colon epithelial cells and in polarized Madin–Darby canine kidney cells. We determine the kinetic parameters of SMCT activity and show its inhibition by ibuprofen ( K i = 73 ± 9 μM) in Xenopus laevis oocytes. SMCT was proposed to be a tumor suppressor in colon cancer [Li, H., et al. (2003) Proc. Natl. Acad. Sci. USA 100, 8412–8417]. Significantly, we show that higher expression of SMCT in colon samples from 113 colorectal cancer patients correlates with longer disease-free survival, suggesting that SMCT expression may be a favorable indicator of colorectal cancer prognosis.

The KCNQ1 α subunit and the KCNE2 βsubunit form a potassium channel in thyroid epithelial cells. Genetic disruption of KCNQ1-KCNE2 causes hypothyroidism in mice, resulting in cardiac hypertrophy, dwarfism, alopecia, and prenatal mortality. Here, we investigated the mechanistic requirement for KCNQ1-KCNE2 in thyroid hormone biosynthesis, utilizing whole-animal dynamic positron emission tomography. The KCNQ1-specific antagonist (-)-[3R,4S]- chromanol 293B (C293B) significantly impaired thyroid cell I- uptake, which is mediated by the Na+/I- symporter (NIS), in vivo (dSUV/dt: vehicle, 0.028±0.004 min-1; 10 mg/kg C293B, 0.009±0.006 min-1) and in vitro (EC50: 99±10 μM C293B). Na+-dependent nicotinate uptake by SMCT, however, was unaffected. Kcne2 deletion did not alter the balance of free vs. thyroglobulin-bound I- in the thyroid (distinguished using ClO 4-, a competitive inhibitor of NIS), indicating that KCNQ1-KCNE2 is not required for Duox/TPO-mediated I- organification. However, Kcne2 deletion doubled the rate of free I- efflux from the thyroid following ClO4- injection, a NIS-independent process. Thus, KCNQ1-KCNE2 is necessary for adequate thyroid cell I- uptake, the most likely explanation being that it is prerequisite for adequate NIS activity. © FASEB. Fil: Purtell, Kerry. Weill Cornell Medical College; Estados Unidos Fil: Paroder-Belenitsky, Monika. Yeshiva University; Estados Unidos Fil: Reyna-Neyra, Andrea. Yeshiva University; Estados Unidos Fil: Nicola, Juan Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina. University of Yale; Estados Unidos Fil: Koba, Wade. Yeshiva University; Estados Unidos Fil: Fine, Eugene. Yeshiva University; Estados Unidos Fil: Carrasco, Nancy. Yeshiva University; Estados Unidos. University of Yale; Estados Unidos Fil: Abbott, Geoffrey W.. Weill Cornell Medical College; Estados Unidos

Aim The purpose of this study is to report a case of endogenous endopthalmitis caused by Scedosporium apiospermum with a favorable outcome and review previously reported cases, their treatment regimens and outcomes. Methods An 83-year-old man with diabetes mellitus, no other immunocompromising risk factors, and a history of S. apiospermum endopthalmitis in the left eye developed endopthalmitis in the right eye. Within 72 h of presentation, he was treated with a pars plana vitrectomy and intravitreal voriconozole. Results Vitreous cultures confirmed S. apiospermum. The patient responded to treatment, with a favorable outcome and full recovery of vision. Conclusions Recognition of S. apiospermum endopthalmitis and appropriate early intervention with pars plana vitrectomy and intravitreal voriconozole can lead to a favorable outcome with restoration of visual acuity.

Absorption of dietary iodide, presumably in the small intestine, is the first step in iodide (I−) utilization. From the bloodstream, I−is actively taken up via the Na+/I−symporter (NIS) in the thyroid for thyroid hormone biosynthesis and in such other tissues as lactating breast, which supplies I−to the newborn in the milk. The molecular basis for intestinal I−absorption is unknown. We sought to determine whether I−is actively accumulated by enterocytes and, if so, whether this process is mediated by NIS and regulated by I−itself. NIS expression was localized exclusively at the apical surface of rat and mouse enterocytes. In vivo intestine-to-blood transport of pertechnetate, a NIS substrate, was sensitive to the NIS inhibitor perchlorate. Brush border membrane vesicles accumulated I−in a sodium-dependent, perchlorate-sensitive manner with kinetic parameters similar to those of thyroid cells. NIS was expressed in intestinal epithelial cell line 6, and I−uptake in these cells was also kinetically similar to that in thyrocytes. I−downregulated NIS protein expression and its own NIS-mediated transport both in vitro and in vivo. We conclude that NIS is functionally expressed on the apical surface of enterocytes, where it mediates active I−accumulation. Therefore, NIS is a significant and possibly central component of the I−absorption system in the small intestine, a system of key importance for thyroid hormone biosynthesis and thus systemic intermediary metabolism.

Background The sodium/iodide symporter (NIS) is a plasma membrane glycoprotein that mediates iodide (I-) transport in the thyroid, lactating breast, salivary glands, and stomach. Whereas NIS expression and regulation have been extensively investigated in healthy and neoplastic thyroid and breast tissues, little is known about NIS expression and function along the healthy and diseased gastrointestinal tract. Methods Thus, we investigated NIS expression by immunohistochemical analysis in 155 gastrointestinal tissue samples and by immunoblot analysis in 17 gastric tumors from 83 patients. Results Regarding the healthy Gl tract, we observed NIS expression exclusively in the basolateral region of the gastric mucin-producing epithelial cells. In gastritis, positive NIS staining was observed in these cells both in the presence and absence of Helicobacter pylori. Significantly, NIS expression was absent in gastric cancer, independently of its histological type. Only focal faint NIS expression was detected in the direct vicinity of gastric tumors, i.e., in the histologically intact mucosa, the expression becoming gradually stronger and linear farther away from the tumor. Barrett mucosa with junctional and fundic-type columnar metaplasia displayed positive NIS staining, whereas Barrett mucosa with intestinal metaplasia was negative. NIS staining was also absent in intestinalized gastric polyps. Conclusion That NIS expression is markedly decreased or absent in case of intestinalization or malignant transformation of the gastric mucosa suggests that NIS may prove to be a significant tumor marker in the diagnosis and prognosis of gastric malignancies and also precancerous lesions such as Barrett mucosa, thus extending the medical significance of NIS beyond thyroid disease.

In T cells anergy may be evoked by an unbalanced stimulation of the T-cell receptor in the absence of costimulation. Anergic T cells are unresponsive to new antigen receptor engagement and do not produce interleukin 2. We present evidence that anergizing stimuli induce changes in histone acetylation, which mediates transcriptional repression of interleukin 2 expression. In response to calcium signaling, anergic T cells up-regulate the expression of Ikaros, a zinc finger transcription factor essential for lymphoid lineage determination. Ikaros binds to the interleukin 2 promoter where it induces histone deacetylation. Confirming the role of Ikaros in the induction of T-cell anergy, cells with reduced Ikaros activity show defective inactivation in response to an anergizing stimulus. We propose a model in which tolerizing stimuli induce epigenetic changes on the interleukin 2 locus that are responsible for the stable inhibition of the expression of this cytokine in anergic T cells.