Absolute CD4 Counts Research Articles

Treatment with oclacitinib, a Janus kinase inhibitor, down-regulates and up-regulates CD25 and Foxp3 expression, respectively, in peripheral blood T cells of dogs with atopic dermatitis

BackgroundOclacitinib (OCL), a Janus kinase inhibitor, is a novel immunomodulatory/immunosuppressive agent which is an approved as the first-line treatment for atopic dermatitis (AD) in dogs. The aim of the study was to investigate the effects of OCL on CD4+ and CD8+ T cells and their selected subsets under clinical conditions, i.e. in dogs suffering from AD, in terms of both safety and immune mechanisms underlying its therapeutic actions. Eight dogs were treated for 28 days with OCL at the recommended dose. Blood samples were taken at day 0, 7, 14 and 28.ResultsThe study showed that the mean percentage and absolute count of CD4+ and CD8+ T cells on the 14th and 28th day of the treatment with OCL did not differ from the corresponding baseline values, i.e. those before the treatment. On the 7th day of the treatment, the mean absolute count of CD4+ T cells and the mean percentage and absolute count of CD8+ T cells were significantly increased. The research found that on the 14th day of the treatment, the mean percentage and absolute count of CD25+CD4+ and CD25+CD8+ T cells were significantly decreased; the reduction in the percentage of CD25+CD4+ T cells persisted on 28th day of the treatment. A two-week treatment with OCL resulted in an increase in the mean percentage of Foxp3+CD4+ T cells, and this effect was sustained at the last time point. The treatment with OCL decreased the eosinophil level but does not affect the absolute counts of basophils, monocytes and neutrophils.ConclusionsThe findings of the study strongly suggest that: (a) in terms of the impact of OCL on the number of PB CD4+ and CD8+ T cells, monthly treatment with the drug should be considered as a relatively safe; (b) the eosinophil-reducing effect and the down-regulation of the AD up-regulated CD25 expression on CD4+ Teff cells may constitute significant elements of the mechanism of action underlying the therapeutic effects of the drug in the treatment of canine AD; (c) the generation of inducible Foxp3-expressing CD4+ regulatory T cells - resulting in the shift of the CD4+ Treg cell (i.e. Foxp3+CD4+)/activated Teff (i.e. CD25+CD4+) cell balance toward an increased proportion of Treg cells - may be considered as additional mechanism involved in producing the immunomodulatory/immunosuppressive properties of OCL.

Evaluation of CMV T-cell Mediated Immunity in Children with CMV DNAemia After Allogeneic Hematopoietic Cell Transplantation

Abstract Background Cytomegalovirus (CMV) is among the most common infectious complications following allogeneic hematopoietic cell transplantation (allo-HCT). A commercially available CMV T-cell immune panel (CMV-TCIP, Viracor®), reported as percentages of CMV-specific interferon gamma releasing CD4 and CD8 cells (%CMV-CD4 or %CMV-CD8 IFN-γ), may be used to assess CMV cell-mediated immunity (CMV-CMI). However, the utility of this assay among pediatric allo-HCT recipients remains unknown. Methods A retrospective analysis among pediatric allo-HCT recipients (age ≤18 years) from 1/2020 to 11/2023 who developed CMV DNAemia and had CMV-TCIP testing was performed. Per institutional protocol, weekly quantitative plasma CMV PCR was performed until day +100. Clinically significant CMV infection (csCMVi) was defined as CMV viral load (VL) ≥500IU/ml and pre-emptive therapy (PET) was provided for csCMVi. The most frequent indications for CMV-TCIP testing were to evaluate CMV-CMI to inform the need of CMV virus-specific T-cell therapy (CMV-VST) in the setting of resistant/refractory CMV, to monitor CMV-CMI as a proxy of VST expansion post CMV-VST, or to evaluate the need of ongoing secondary antiviral prophylaxis. A %CMV-CD4 or %CMV-CD8 IFN-γ ≤0.2% was categorized as a poor response, whereas a result >0.2% was classified as an adequate response. Specimens with insufficient quality, high background, or discrepant results from %CMV-CD4 or %CMV-CD8 were classified as a discordant response. Demographics, underlying condition, HCT type, conditioning regimen, antiviral agents and use of VST, VL, and CMV-TCIP results were recorded. Descriptive and nonparametric statistics (median, interquartile range [IQR]) were used for analysis. Results Twenty-seven CMV-TCIP results from 10 unique allo-HCT recipients were analyzed. The median age at transplant was 8.5 years (IQR 2.75-14.3), predominantly for hematologic malignancy (70%). CMV donor/recipient (D/R) serostatus were D+/R+ (60%), D-/R+ (30%) and D+/R- (10%). CMV DNAemia developed post-HCT in 80% (8/10) with median onset of 4 days post-HCT (IQR 3-40) and 2 subjects had known DNAemia prior to HCT. Nine (90%) subjects were started on PET for csCMVi, whereas 1 (10%) received antiviral therapy when VL was <500IU/ml. The first CMV-TCIP was obtained at median of 112 days (IQR 42-130) post-HCT. Despite appropriate antiviral therapy, patients with a peak VL ≥500 IU/mL (obtained within 1 week before and after CMV-TCIP testing) demonstrated significantly lower absolute CD4 (median 12 vs. 198 cells/uL, p=0.02) and CD8 (median 79 vs. 443 cells/uL, p=0.04) counts and %CMV-CD4 IFN-γ (0.04% vs. 0.36%, p=0.02) compared to those with a peak VL <500 IU/mL. Conclusion Our results suggest that CMV-CMI, particularly %CMV-CD4 IFN-γ >0.2%, was observed concurrently with downward trending VL, and may serve as a proxy of VST expansion in patients receiving CMV-VSTs. Figure 1A. The distribution of peak VLs over time based on %CMV-CD4 and %CMV-CD8 IFN-γ are demonstrated in Figure 1B. CMV peak VLs were lower with TCIP testing results reported as adequate combined responses compared to those with poor combined responses. In five subjects (50%) who received CMV-VSTs as part of CMV therapy, increased %CMV-CD4 and %CMV-CD8 IFN-γ were observed post-infusion with an observed downward trend in VL.

Bidirectional Mendelian Randomization Reveals Causal Effects of Immune Cell Traits on Endometriosis Risk.

Previous studies have identified associations between immune cell traits and endometriosis, but the causality of these relationships remains uncertain. In this study, we utilized Mendelian randomization (MR) to investigate the causal relationship between immune cell traits and endometriosis for the first time. Seven hundred and thirty-one immune cell signatures associated with single-nucleotide polymorphisms (SNPs) were extracted from a published genome-wide association study (GWAS) involving 472174 individuals, while endometriosis data, including four stages and seven subtypes, were obtained from the FinnGen consortium. Four methods were used for MR. The causal effect of immune cell traits on endometriosis was explored after Bonferroni correction. Significant causal relationship included 92 immune cell traits distributed among B cell (28 cells), cDC (2 cells), maturation stages of T cell (10 cells), monocyte (12 cells), Myeloid cell (5 cells), TBNK (13 cells), and Treg panels (22 cells). One of the most significant findings is that for every 1-standard deviation (SD) increase in CD8 on Central Memory CD8+ T cell, the risks of developing endometriosis of the fallopian tube increased by 72%. In the reverse MR analysis, a one-unit increase in the log odds of endometriosis of the ovary risk corresponded to a decrease in the absolute count of CD4+ CD8dim T cell by 0.10. This study represents the first comprehensive evaluation of the causal effects of immune cell traits on the risk/protection of different stages/subtypes of endometriosis. The findings highlight the complex and significant role of immune-derived factors in the pathogenesis of the disease.

Management of Stage-4 HIV with Cerebral Toxoplasmosis Coinfection and SIADH Complication

HIV/AIDS stage 4 is the stage where the HIV/AIDS patients have low immunity protection against infections, which can led to coinfections and complications. This case report presented an evaluation of the diagnosis and treatment of an HIV/AIDS stage 4 patient with cerebral toxoplasmosis coinfection and SIADH complications. A man (47 years, 35 kg), married with two children, complaining of weakness, nausea, vomiting, weight loss, and low appetite. Sodium level were measured, showing a 117 mg/dL level that continued to decrease throughout the patient's treatment. Five days later, the patient lost his consciousness with a GCS score of 224, indicating severe brain injury, and was diagnosed with cerebral toxoplasmosis based on the result of head CT-SCAN with contrast. On day 6, the patient was tested positive for HIV and diagnosed with stage 4 with an absolute CD4 count of 4 cells/μl. Therapy was provided by giving pyrimethamine-clindamycin therapy for cerebral toxoplasmosis, followed by Tenofovir, Lamivudine, and Evafirenz as antiretroviral therapy. Treatment for hyponatremia was done by administration of 3% NaCl and tolvaptan. The patient started experiencing an improvement in consciousness after the 10th day of medication, and sodium levels fluctuated throughout the treatments. Patient was discharged after 15 days with clinical improvements.

Sleep actigraphy results and HIV health outcomes in an urban HIV clinic sample

ABSTRACT Sleep disorders are prevalent and interfering conditions that affect people living with HIV (PLWH) at higher rates than the general population. Lower quality sleep has been associated with poorer health-related quality of life and immune function in PWH, though sleep is typically assessed subjectively. The current study aimed to examine the association between objective sleep/wake patterns measured via actigraphy with HIV outcomes. Participants (N = 87) were recruited from a public, urban HIV clinic located in the Southeastern United States. Participants were instructed to wear actigraphy monitors for one week (Range: 5–8 days). Log viral load and absolute CD4 were obtained via medical chart review. Linear regression analyses predicting HIV RNA Viral Load (log transformed) and CD4 Count were employed with three actigraphy sleep variables: sleep efficiency, wake after sleep onset (WASO), and sleep quantity. Backward entry regression with both significant actigraphy predictors, sleep efficiency and WASO, included as predictors resulted in sleep efficiency remaining in the model and WASO being removed. Separate models revealed that each one-unit increase in sleep efficiency was associated with a b = 0.032-point decrease in the log-transformed HIV RNA viral load (p = 0.03) and for each one-unit increase in wake after sleep onset (WASO) was associated with a b = 0.35-point increase in the log-transformed HIV RNA viral load (p = 0.04). Sleep quantity, however, was not, and none were associated with absolute CD4 count. The findings add to the evidence for an association of objectively measured poorer sleep efficiency being associated with higher HIV RNA viral load. Implications for clinical practice include assessing and addressing sleep efficiency as part of comprehensive clinical HIV care.

Revisiting double-negative T cells in autoimmune lymphoproliferative immunodeficiencies: a case series.

Elevated level of double-negative T (DNT) cells is a historical hallmark of autoimmune lymphoproliferative syndrome (ALPS) diagnosis. However, the peripheral blood level of DNT cells might also be compromised in autoimmune lymphoproliferative immunodeficiencies (ALPID) other than ALPS, inattention to which would increase the delay in diagnosis of the underlying genetic defect and hinder disease-specific treatment. This cross-sectional study recruited patients suffering from ALPID (exclusion of ALPS) with established genetic diagnosis. Following thorough history taking, immunophenotyping for lymphocyte subsets was performed using BD FACS CaliburTM flowcytometry. Fifteen non-ALPS ALPID patients (60% male and 40% female) at a median (interquartile range: IQR) age of 14.0 (7.6-21.8) years were enrolled. Parental consanguinity and family history of immunodeficiency were present in 8 (53.3%) patients. The median (IQR) age at first presentation, clinical and molecular diagnosis were 18 (4-36) months, 8.0 (4.0-17.0) years, and 9.5 (5.0-20.9) years, respectively. Molecular defects were observed in these genes: LRBA (3, 20%), CTLA-4 (2, 13.3%), BACH2 (2, 13.3%), AIRE (2, 13.3%), and FOXP3, IL2Rβ, DEF6, RASGRP1, PIK3CD, and PIK3R1 each in one patient (6.7%). The most common manifestations were infections (14, 93.3%), autoimmunity (12, 80%), and lymphoproliferation (10, 66.7%). The median (IQR) count of white blood cells (WBCs) and lymphocytes were 7160 (3690-12,600) and 3266 (2257-5370) cells/mm3, respectively. The median (IQR) absolute counts of CD3+ T lymphocytes and DNTs were 2085 (1487-4222) and 18 (11-36) cells/mm3, respectively. Low lymphocytes and low CD3+ T cells were observed in 3 (20%) patients compared to normal age ranges. Only one patient with FOXP3 mutation had DNT cells higher than the normal range for age. Most non-ALPS ALPID patients manifested normal DNT cell count. For a small subgroup of patients with high DNT cells, defects in other IEI genes may explain the phenotype and should be included in the diagnostic genetic panel.

Posterior Segment Manifestations of Syphilis and Correlation With Serologic Markers of Infection.

Retrospective analysis correlating serologic titers of ocular syphilis with posterior segment manifestations. This study consisted of 40 patients (80 eyes imaged, 68 affected) with positive rapid plasma reagin (RPR) and Treponema Pallidum immunoglobulin G. We collected demographic and presentation data including HIV status, absolute CD4 count, RPR, cerebrospinal fluid-venereal disease research laboratory (CSF-VDRL) test, and retinal zone. We categorized imaging into syphilitic outer retinopathy (SOR), acute syphilitic posterior placoid chorioretinopathy, retinitis/chorioretinitis (RC), and papillitis. Multivariate analysis correlated HIV status, RPR, and VDRL titers with posterior segment findings and zone. Mean age of 42.8 ± 10.7 years, with 70% male patients. Presenting visual acuity (logMAR) 0.66 ± 0.74 did not correlate with RPR, nor was it associated with papillitis, RC, or acute syphilitic posterior placoid chorioretinopathy. Higher RPR (≥ 1:128) positively associated with SOR (P = 0.031) and zone 1 (odds ratio [OR], 1.62; P = 0.02), but negatively associated with zone 2 (OR 0.35; P = 0.005). HIV positivity increased RC odds (OR, 4.45; P = 0.047). Higher RPR correlated with SOR and zone 1, whereas HIV positivity correlated with RC. [Ophthalmic Surg Lasers Imaging Retina 2024;55:511-516.].

Longitudinal Study of Cognitive Function in People with HIV and Toxoplasmic Encephalitis or Latent toxoplasma Infection.

Neurocognitive impairment (NCI) may occur during and persist even after recovery from HIV-related CNS co-infections such as toxoplasmic encephalitis (TE). The long-term cognitive effects of TE and latent toxoplomasmic infections (LTI) among persons with HIV (PWH) are unknown. We measured longitudinal effects on NC functioning in PWH with TE compared to LTI or no toxoplasmal infection. PWH (n = 345) followed in two longitudinal cohort studies underwent comprehensive neurocognitive assessments and an anti-Toxoplamic IgG assay. Participants were classified into one of three groups: TE+ (n = 39), LTI+ (n = 34), LTI- (n = 272). The primary outcome was change in neurocognitive function between baseline and 7-year visit. The mean age was 48 ± 11 years, mean educational level 13 ± 3 years, and 13% were female. TE+ patients were less likely to have undetectable viral loads (≤50 copies/mL) and had lower absolute CD4 counts. The TE+ group had the highest prevalence of NCI globally and in domains of verbal, executive function, learning, recall, working memory, processing speed and motor at baseline and at 7-year follow-up. Changes in longitudinal NC function over 7 years were small and did not differ significantly among all groups, except that speed of information processing improved more in TE+ compared with LTI- participants. PWH with a history of TE had cognitive impairment over a broad range of severity at both baseline and last follow-up. Changes in cognition from baseline to last examination in all groups were minimal and did not differ significantly among the groups with the exception of speed of information processing.

Prospective Study of the Recovery of CD4+ T cell Subsets and Their Relationship to the Overall Survival Following Allogeneic Hematopoietic Stem Cell Transplantation.

The immune recovery (IR) following the allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an advancement procedure that fundamentally correlated to the curative success. It is critical to understand the interfering factors in IR to prevent the HSCT-related mortality. The factors influencing CD4+T cell recovery post (HSCT) are not well totally characterized. This work was conducted to analyze the kinetics of CD4+T cell subsets recovery post HSCT, and to correlate their reconstitution with different factors that may influence the overall survival following HSCT. We prospectively evaluated the clinical outcomes and CD4+ T lymphocyte subtypes regeneration kinetics at different time-points of 22 patients with allogeneic HSCT for malignant and non-malignant diseases from 2007 to 2008. Statistics (means, minimal, and maximal values) were used to describe patient baseline characteristics. Results were presented as absolute count of CD4+ T cells, % of naive and memory subsets, and p-values. Thymus-independent pathways were responsible for the rapid recovery of memory CD4+T cells less than 6 months after HSCT. Thymus-dependent pathways were activated between 6 and 12 months in the majority of patients with increasing counts of naive CD4+ T cell. Furthermore, increasing patient age and chronic GVHD predicted the slow naive T cell recovery and also predicted high memory T cell numbers. The proper CD4 + reconstitution was associated with younger age, a non-malignant disease and a lower incidence of acute graft-versus-host disease ≥ grade 2. Additionally, the CD4+ T lymphocytes recovery ≥ 200/µl was associated with a higher overall survival. Different factors affected the IR post the allo-HSCT. The CD4+ count ≥ 200/µl was a simple IR predictor of overall survival and better clinical outcome following allogeneic HSCT.

New pharmacodynamic parameters linked with ibrutinib responses in chronic lymphocytic leukemia: Prospective study in real-world patients and mathematical modeling.

One of the first clinical observations of ibrutinib activity in the treatment of chronic lymphocytic leukemia (CLL) is a rapid decline in lymph nodes size. This phenomenon is accompanied by an hyperlymphocytosis, either transient or prolonged, which is associated with distinct clinical responses and thus has an impact on long-term outcomes. Understanding which factors determine distinct disease courses upon ibrutinib treatment remains a scientific challenge. From 2016 to 2021, we conducted a longitudinal and observational study in 2 cohorts of patients with chronic lymphocytic leukemia (CLL) (cohort 1, n = 41; cohort 2, n = 81). These cohorts reflect the well-known clinical features of CLL patients, such as Male/Female sex ratio of 2/1, a median age of 70 years at diagnosis, and include patients in first-line therapy (27%) or relapsed/refractory patients (73%). Blood cell counts were followed for each patient during 2 years of ibrutinib treatment. In addition, immunophenotyping and whole-body magnetic resonance imaging (MRI) were assessed in patients from cohort 1. These data were integrated in a newly built mathematical model, inspired by previous mathematical works on CLL treatment and combining dynamical and statistical models, leading to the identification of biological mechanisms associated with the 2 types of clinical responses. This multidisciplinary approach allowed to identify baseline parameters that dictated lymphocytes kinetics upon ibrutinib treatment. Indeed, ibrutinib-induced lymphocytosis defined 2 CLL patient subgroups, transient hyperlymphocytosis (tHL) or prolonged hyperlymphocytosis (pHL), that can be discriminated, before the treatment, by absolute counts of CD4+ T lymphocytes (p = 0.026) and regulatory CD4 T cells (p = 0.007), programmed cell death protein 1 PD1 (p = 0.022) and CD69 (p = 0.03) expression on B leukemic cells, CD19/CD5high/CXCR4low level (p = 0.04), and lymph node cellularity. We also pinpointed that the group of patients identified by the transient hyperlymphocytosis has lower duration response and a poor clinical outcome. The mathematical approach led to the reproduction of patient-specific dynamics and the estimation of associated patient-specific biological parameters, and highlighted that the differences between the 2 groups were mainly due to the production of leukemic B cells in lymph node compartments, and to a lesser extent to T lymphocytes and leukemic B cell egress into bloodstream. Access to additional data, especially longitudinal MRI data, could strengthen the conclusions regarding leukemic B cell dynamics in lymph nodes and the relevance of 2 distinct groups of patients. Altogether, our multidisciplinary study provides a better understanding of ibrutinib response and highlights new pharmacodynamic parameters before and along ibrutinib treatment. Since our results highlight a reduced duration response and outcome in patients with transient hyperlymphocytosis, our approach provides support for managing ibrutinib therapy after 3 months of treatment. ClinicalTrials.gov NCT02824159.

Immune effect and prognosis of transcatheter arterial chemoembolization and tyrosine kinase inhibitors therapy in patients with hepatocellular carcinoma.

The combination of transcatheter arterial chemoembolization (TACE) and tyrosine kinase inhibitors (TKIs) has shown broad prospects in prolonging the survival of patients with hepatocellular carcinoma (HCC). TACE and TKIs can affect the immune microenvironment in patients with HCC. To determine the overall effects and differences between TACE and different TKIs combinations on the immune microenvironment. Data and immune cell profile test results from 213 HCC patients treated with TACE combined with apatinib, lenvatinib, sorafenib, or donafenib before and after 3 wk of treatment were collected. Monocytes were co-cultured with LM3 liver cancer cells, and their ability to inhibit cancer cell growth was analyzed using the MTT method and a nude mouse subcutaneous tumorigenesis experiment. Simulated combined therapy was done using an in situ liver cancer C57BL/6 male mouse model, and the immune response of tumor tissues was analyzed using immunohistochemistry. Compared to before combination therapy, the proportion of programmed cell death protein 1 (PD-1)+ mononuclear cells and the number of CD4+ T cells decreased in the TACE + apatinib group, while the number of absolute count of CD4+ and CD8+ T cells increased in the TACE + lenvatinib group. Furthermore, the number of regulatory cells decreased in the TACE + donafenib group, whereas the number of CD8+ T and natural killer cells increased. Additionally, monocytes in the TACE combined with donafenib or lenvatinib groups had a stronger ability to inhibit cancer cell growth than those in the other groups. Combining TACE with donafenib or lenvatinib increased CD8+ T cell infiltration into the tumor tissue. In addition, the proportion of PD-1+ in CD8+ cells, absolute CD8+ T lymphocyte count, and regulatory T cells proportion were independent prognostic factors affecting the survival time of patients with HCC. TACE, in combination with different TKIs, produces different immune responses. Specifically, TACE combined with donafenib or lenvatinib may induce strong anti-tumor immune responses.

P-015 Impaired spermatogenesis in colitis: the role of interferon-γ mediated ferroptosis in sertoli cells by colitic CD4+ T cells

Abstract Study question Does colitis have an impact on spermatogenesis and what could be the potential mechanism? Summary answer Colitis causes sertoli cell ferroptosis and disrupts spermatogenesis in mice due to the migration of colitic CD4+ T cells that produce interferon-γ. What is known already In recent years, there has been a significant increase in rheumatic and inflammatory diseases. Epidemiological data reveals that dysregulated immune conditions can directly or indirectly impact male fertility and sexual function in patients of reproductive age. Inflammatory bowel disease (IBD), which encompasses Crohn’s disease and ulcerative colitis, is a chronic, recurring gastrointestinal inflammatory disorder characterized by bloody stools and weight loss. A study from a Swedish national cohort showed that IBD patients had diminished sperm fertility and increased sperm DNA fragmentation compared to healthy individuals. However, the precise mechanisms underlying male fertility problems in IBD remain unclear. Study design, size, duration In this study, C57BL/6 mice were kept under specific pathogen-free conditions. A murine colitis model that simulates human colitis histological features and symptoms was created using Dextran Sulfate Sodium (DSS). To establish the model, 2-2.5% DSS was added to the mice’s drinking water from days 0 to 7, followed by a three-day recovery period. Participants/materials, setting, methods Testis, epididymis and colon sections were stained with hematoxylin and eosin for histological analysis. The localization and phenotype of infiltrated lymphocytes in epididymis and testis were studied by immunostaining and flow cytometry. Sperm functions including motility, viability, and DNA integrity were assessed by standard assays. Iron, malondialdehyde, and reactive oxygen species (ROS) levels were analysed by commercial kit. Main results and the role of chance Colitis was found to impair male fertility in DSS-induced colitic mice, causing testis and epididymis tissue damage along with inflammatory cell infiltration. Colitis altered the immune cell phenotypes in the testis and epididymis. The proportion and absolute cell count of CD4+ T cells and CD19+ B cells increased after colon inflammation. Testicular sertoli cells in colitic mice exhibited ferroptosis, characterized by increased levels of iron deposition, malondialdehyde, and ROS. We assessed sperm parameters from the cauda epididymis of mice. Compared to the control group, there were significant reduction in sperm concentration, motility, viability and DNA integrity in the group with murine colitis induction. Consistently, we observed lower numbers of active pups from the fathers of the colitis group compared to control mice. CD4+ T cells with interferon-γ producing capabilities accumulated in the testes of colitis mice. Leukocyte flow cytometric analysis and parabiotic mouse model further demonstrated that colitis promoted pathogenic CD4+ T cells migration to the testis through circulation. The treatment of anti-CD4 antibody, anti-interferon-γ antibody or ferroptosis inhibitor can attenuate the colitis-associated testis pathologies. Limitations, reasons for caution Our study was conducted exclusively in mice. The pathogenic effect and the corresponding mechanism of colitis on male fertility in humans still needs to be confirmed. Wider implications of the findings Our team identified the mechanism linking dysregulated gut immune cell activity to testicular dysfunction. By identifying specific molecules on colitic immune cells, which allow their infiltration into the testis, may pave the way for a new therapeutic approach potentially improving the prognosis of colitis and related fertility impairments. Trial registration number not applicable

A Case of Disseminated Cryptococcus in an HIV-Positive Patient

A 69-year-old male with a history of untreated Human Immunodeficiency Virus (HIV) was admitted to the emergency department for symptoms such as cough, shortness of breath, lethargy, and weight loss. His physical examination revealed severe wasting, oral thrush, and hypoxia. Chest imaging revealed cavitary lesions and blood work showed an absolute CD4 count of 23 cells/mm3. An IR-guided biopsy revealed abundant necrosis and scattered narrow-based fungal organisms consistent with Cryptococcus neoformans infection. The patient was treated with liposomal amphotericin B and flucytosine. Due to the increased risk of Immune Reconstitution Inflammatory Syndrome (IRIS), HIV treatment was deferred. The patient deteriorated, transitioned to comfort care, and unfortunately expired. INTRODUCTION Cryptococcus neoformans is a ubiquitous environmental yeast and a leading cause of invasive fungal infection in humans with significant morbidity and mortality that affects both immunocompetent and immune-compromised hosts.1,2 Globally, there are approximately 1 million cases of AIDS-related cryptococcosis each year, leading to over 600,000 deaths. This represents a prevalence of 6.0% (95% CI 5.8–6.2) among people with a CD4 cell count of less than 100 cells per uL.2 The transmission mode is by inhalation of microscopic fungus (desiccated yeast or spores). Immunosuppression is the strongest risk factor for disease development, including HIV infection, stem cell and solid organ transplantation, prolonged immunosuppressive therapy, invasive medical procedures, hematological malignancies, advanced age, and prematurity.1,2,3 Treatment usually involves a fungicidal regimen of IV liposomal amphotericin B, plus flucytosine followed by oral fluconazole.4,5 Overall, 90-day all-cause mortality in patients with cryptococcal infection is 19.4%. Mortality rates are significantly higher in HIV/transplant patients at 90 days (41.7% versus 8.3%, p = 0.017) and one year (41.7% versus 12.5%, p = 0.047).6,7 This case describes a 69-year-old HIV-positive patient who presented with multisystemic manifestations and cavitary lung lesions with blood and cerebrospinal fluid (CSF) findings of cryptococcal antigen and positive fungal culture and lung biopsy confirmation of Cryptococcus.

Absolute CD4 count and percentage values among Libyan patients with HIV by single-platform flow cytometry.

Single-platform flow cytometry technology together with CD45-gating is becoming the method of choice for absolute CD4 T cell enumeration. Immunological assessment of HIV patients by monitoring CD4 can provide valuable information on antiviral treatment response and disease progression. A total of 97 HIV-positive individuals were recruited from 2 hospitals in Tripoli, Libya, and 14 healthy blood donors. The HIV-infected individuals were classified by CD4+ count into HIV-positive (>200 cells/µL) or AIDS (≤200 cells/µL) groups. CD4+ and CD8+ cell counts were determined and compared among the groups and with similar published data. The mean ± SD CD4+ cell counts were 1106 ± 442.8 cells/µL in healthy individuals, 460 ± 219.7 cells/µL in the HIV-positive group, and 78 ± 64.3 cells/µL in the AIDS group. The mean ± SD CD4+/CD8+ ratio was 1.6 ± 0.58, 0.4 ± 0.22, and 0.1 ± 0.1, respectively. CD4+ counts in Libyan healthy adults might be higher than those reported in several studies in other regions, whereas CD4+ counts in Libyan AIDS patients seem lower. Reference values for T lymphocyte counts in Libyan healthy individuals should be investigated more extensively, and the reasons why Libyan AIDS patients seem to have such lower CD4+ counts should be examined.

Two nomograms constructed for predicting the efficacy and prognosis of advanced non‑small cell lung cancer patients treated with anti‑PD‑1 inhibitors based on the absolute counts of lymphocyte subsets

BackgroundPatients treated with immune checkpoint inhibitors (ICIs) are at risk of considerable adverse events, and the ongoing struggle is to accurately identify the subset of patients who will benefit. Lymphocyte subsets play a pivotal role in the antitumor response, this study attempted to combine the absolute counts of lymphocyte subsets (ACLS) with the clinicopathological parameters to construct nomograms to accurately predict the prognosis of advanced non-small cell lung cancer (aNSCLC) patients treated with anti-PD-1 inhibitors.MethodsThis retrospective study included a training cohort (n = 200) and validation cohort (n = 100) with aNSCLC patients treated with anti-PD-1 inhibitors. Logistic and Cox regression were conducted to identify factors associated with efficacy and progression-free survival (PFS) respectively. Nomograms were built based on independent influencing factors, and assessed by the concordance index (C-index), calibration curve and receiver operating characteristic (ROC) curve.ResultIn training cohort, lower baseline absolute counts of CD3+ (P < 0.001) and CD4+ (P < 0.001) were associated with for poorer efficacy. Hepatic metastases (P = 0.019) and lower baseline absolute counts of CD3+ (P < 0.001), CD4+ (P < 0.001), CD8+ (P < 0.001), and B cells (P = 0.042) were associated with shorter PFS. Two nomograms to predict efficacy at 6-week after treatment and PFS at 4-, 8- and 12-months were constructed, and validated in validation cohort. The area under the ROC curve (AUC-ROC) of nomogram to predict response was 0.908 in training cohort and 0.984 in validation cohort. The C-index of nomogram to predict PFS was 0.825 in training cohort and 0.832 in validation cohort. AUC-ROC illustrated the nomograms had excellent discriminative ability. Calibration curves showed a superior consistence between the nomogram predicted probability and actual observation.ConclusionWe constructed two nomogram based on ACLS to help clinicians screen of patients with possible benefit and make individualized treatment decisions by accurately predicting efficacy and PFS for advanced NSCLC patient treated with anti-PD-1 inhibitors.

Cardiotoxicity in tumor-bearing mice receving thoracic radiation plus tumor radiation and PD-1 inhibitor therapy.

e20509 Background: At present, most preclinical studies explore the cardiotoxicity caused by radiotherapy combined with Anti-PD1s in tumor-free mice. we assessed the overall cardiotoxicity of radiotherapy combined with Anti-PD1, the possibility that blocking HMGB1 does not affect the anti-tumor effect, and the possibility that radiotherapy combined with Anti-PD1 reduces heart damage in tumor-bearing mice. Methods: 25 tumor-bearing C57BL/6 mice on both hind limbs were treated with anti-PD1 or PBS or Anti-HMGB1 with or without thoracic irradiation 20gy and right hind limb tumor 8gy×3F irradiation. HE staining was used to observe the cardiac structure and morphological changes. Flow cytometry was used to observe the distribution of CD3+, CD4+, CD8+T cells in cardiac and peripheral blood. Cardiac function was examined by echocardiography. The expression of myocardial injury marker LDH in peripheral blood was detected by Elisa. Results: Five group was established:A = Control;B = anti-PD1,C = RT,D = RT+Anti-PD1,E = RT+Anti-PD1+Anti-HMGB1.HE showed the myocardial injury in A(without any treatment) was the most severe,and and B and D was slightly severe than C group, administration of Anti-HMGB1 partially attenuated myocardial injury in D. Elisa showed the LDH of A was highest, B were consistent with D in LDH expression, RT was lower. Cardiac function showed no difference in ejection fraction and fractional shortening in five groups. Peripheral blood flow cytometry showed the absolute counts of CD3+T-cell and cd8+T cells were greatest in B group, followed by A, C, D, and E groups. Absolute CD4+ T cell values were highest in the B. The results of myocardial tissue infiltrating lymphocytes showed that the absolute CD3+T-cell and cd8+T cells counts were biggest in the B group, followed by A, C, D, and Egroups. Absolute CD4+T cell counts were highest in B group. C, D had the best anti-tumor effect, and the use of Anti-HMGB1 partially attenuated the cardiac injury caused by D group. Conclusions: (1)Without any treatment, the cancer cachexia induced by tumor will cause serious damage to myocardial. (2) The overall cardiotoxicity of radiotherapy combined with Anti-PD1 group was only slightly increased compared to RT or anti-PD1 alone. Maybe radiotherapy killed part of the Anti-PD1-activated lymphocytes, only resulting in a slight increase in cardiac infiltrating lymphocytes. Anti-HMGB1 maintain the anti-tumor effect of RT+Anti-PD1 and partially attenuated the cardiac damage. [Table: see text]

Identifying risk factors for severe omicron infection in allogeneic hematopoietic stem cell transplant recipients with hematologic malignancies.

In December 2022, a large-scale epidemic occurred in China due to Omicron variant of SARS-CoV-2. This study explored risk factors for Omicron infection in transplant recipients at our institution and investigated the factors influencing the severity of SARS-CoV-2 Omicron infection among recipients of allo-HSCT. This single-center study investigated totally 63 allogeneic hematopoietic stem cell transplant patients infected with Omicron variant at the Beijing GoBroad Boren Hospital Transplant Center during December 2022 and analyzed their risk factors. The study included 63 allogeneic hematopoietic stem cell transplant patients who developed Omicron infection. There were 34 mild and 29 moderate to severe cases. Their median age was 22 years (range, 1-65 years), with the male-to-female ratio being 1:1.1. Acute myeloid leukemia (53.97%), acute lymphoblastic leukemia (42.86%), and non-Hodgkin lymphoma (3.17%) were underlying diseases. The median time between HCT and Omicron infection was 8.45 months. Significant predictive factors for moderate to severe Omicron infection included older age (p < .0001), cGVHD (p = .0195), concurrent bacterial infection (p < .0001), low absolute lymphocyte count (p = .026), low CD4/CD8 ratio (p = .0091), high CRP (p < .0001), high serum ferritin (p = .0023), high D-dimer (p < .0001), low CD4 absolute count (p = .0057), and low B-cell absolute count (p = .0154). A moderate to high HCT-CI score tended to be associated with moderate to severe infection (p = .0596). This study indicates that risk factors for severe Omicron infection include certain clinical characteristics, such as age, cGVHD, and inflammatory response.

An Uncommon Cause of Elevated Liver Transaminases: Immune Reconstitution Inflammatory Syndrome from Unmasking of Occult Mycobacterium Avium Complex Infection in an HIV Infected Patient

Abnormal liver chemistry from the development of immune reconstitution inflammatory syndrome (IRIS) may reflect an unmasking of subclinical disease. We present the case of a 37-year-old female with a mixed pattern of liver injury from disseminated mycobacterium avium complex infection after starting antiretroviral therapy (ART). Presenting symptoms were fever, confusion, dysphagia, and abdominal discomfort for one week. Exam revealed a fever of 103.2°F, hypotension, encephalopathy, and abdominal tenderness. Lab work was significant for acute normocytic anemia, leukopenia, absolute CD4 count 28 cells/cmm, HIV viral load 276 viral copies/ml (vc/ml), ALT 267 U/L, AST 484 U/L, alkaline phosphatase 342 U/L, and normal total bilirubin. Imaging revealed hepatomegaly with steatosis and mesenteric and retroperitoneal lymphadenopathy. Percutaneous liver biopsy demonstrated noncaseating granulomas with AFB-positive organisms, with AFB blood cultures growing Mycobacterium avium complex (MAC), consistent with disseminated MAC infection. Clinicians must have a high index of suspicion for IRIS when determining the etiology of elevated liver transaminases in patients with HIV.

A phase I trial of autologous RAK cell immunotherapy in metastatic renal cell carcinoma

BackgroundTreatment of metastatic renal cell carcinoma (mRCC) remains a challenge worldwide. Here, we introduced a phase I trial of autologous RAK cell therapy in patients with mRCC whose cancers progressed after prior systemic therapy. Although RAK cells have been used in clinic for many years, there has been no dose-escalation study to demonstrate its safety and efficacy.MethodsWe conducted a phase I trial with a 3 + 3 dose-escalation design to investigate the dose-related safety and efficacy of RAK cells in patients with mRCC whose cancers have failed to response to systemic therapy (ChiCTR1900021334).ResultsAutologous RAK cells, primarily composed of CD8+ T and NKT cells, were infused intravenously to patients at a dose of 5 × 109, 1 × 1010 or 1.5 × 1010 cells every 28 days per cycle. Our study demonstrated general safety of RAK cells in a total of 12 patients. Four patients (33.3%) showed tumor shrinkage, two of them achieved durable partial responses. Peripheral blood analysis showed a significant increase in absolute counts of CD3+ and CD8+ T cells after infusion, with a greater fold change observed in naive CD8+ T cells (CD8+CD45RA+). Higher peak values of IL-2 and IFN-γ were observed in responders after RAK infusion.ConclusionThis study suggests that autologous RAK cell immunotherapy is safe and has clinical activity in previously treated mRCC patients. The improvement in peripheral blood immune profiling after RAK cell infusion highlights its potential as a cancer treatment. Further investigation is necessary to understand its clinical utility.

Abstract 750: Specific oral bacterial profile associated with oral HPV status in Puerto Rican People with HIV

Abstract Human papillomavirus (HPV) accounts for more than 70% of oropharyngeal cancers and people with HIV (PWH) are disproportionately affected by HPV infection even with successful antiretroviral therapy. Puerto Rico (PR) is in the top ten in terms of HIV prevalence in the US, and also has disparities in HPV-related malignancies. The oral microbiome can increase the risk of HPV infection and persistence; however, it has not been investigated in the context of HIV in PR. Therefore, we evaluated diversity and composition of the oral bacteriome of 48 virologically suppressed PWH (men and women ≥21 and &amp;lt;64 years old) living in PR in relation to HPV status (HPV+: n=18 vs. HPV-: n=30). We collected saliva (16S rDNA sequencing), oral rinse (HPV genotyping) as well as sociodemographic, lifestyle and behavioral characteristics. Short chain fatty acids (SCFA, acetate, butyrate and propionate) were quantified using gas chromatography and mass spectrometry. Periodontal disease was assessed by a clinical full-mouth periodontal assessment using the CDC/AAP guidelines. All analyses were performed using QIIME2 and R-statistical software. There were no significant differences in alpha diversity (Shannon, observed OTUs, and Faith) between HPV+ and HPV- groups. Absolute CD4 count was not significantly different between HPV+ and HPV- participants (794 cells/µL vs. 735 cells/µL), and did not correlate with either microbial richness or diversity. Higher microbial richness was associated with lower levels of acetate (r=-0.35, p&amp;lt;0.05) and propionate (r=-0.31, p&amp;lt;0.05,). Additionally, higher phylogenetic diversity was also associated with lower levels of acetate (r=-0.38, p&amp;lt;0.05) and propionate (r=-0.35, p&amp;lt;0.05) irrespective of the HPV status. On the other hand, higher levels of butyrate was significantly associated with higher microbial diversity (Shannon index; r=0.33, p&amp;lt; 0.05). Taxonomic analyses showed significantly higher abundance of Dialister and Nanosynbacter genera in HPV+ participants and higher abundance of Rothia genus and Capnocytophaga sputigena in HPV- participants. Overall, we found specific prokaryotic profile and associated metabolites associated with HPV infection, which may suggest that the oral microbiome could influence the natural history of HPV infection via SCFA signaling. Members of the Dialister genus have been found to be prevalent in Hispanic and Black women cervicovaginal microbiota, and as well as in HPV infection and oral cancer. Understanding the underpinning mechanisms of how the oral microbiome can facilitate HPV infection and persistence in PWH is essential to establish targets for early identification and personalized treatment approaches for oral HPV-related malignancies. Citation Format: Yakshi N. Ortiz-Maldonado, Gabriel Borges-Velez, Jurelis Torres-Reyes, Alvin A. Peralta-Betanncourt, Jeannette L. Salgado-Montilla, Jorge Viera-Vera, Maria M. Sanchez-Vazquez, Magaly Martinez-Ferrer, Ana P. Ortiz-Martinez, Ramon F. Gonzalez-Garcia, Josue Perez-Santiago. Specific oral bacterial profile associated with oral HPV status in Puerto Rican People with HIV [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 750.