Familial CD45RA- T cells to treat severe refractory infections in immunocompromised patients.

Background: Immunocompromised patients are susceptible to high-risk opportunistic infections and malignant diseases. Most antiviral and antifungal drugs are quite toxic, relatively ineffective, and induce resistance in the long term. The transfer of pathogen-specific Cytotoxic T-Lymphocytes has shown a minimal toxicity profile and effectiveness in treating Cytomegalovirus, Adenovirus, Epstein - Barr virus, BK Virus and Aspergillus infections, but this therapy have the main limitations of regulatory issues, high cost, and absence of public cell banks. However, CD45RA- cells containing pathogen-specific memory T-cells involve a less complex manufacturing and regulatory process and are cheaper, feasible, safe, and potentially effective. Methods: We present preliminary data from six immunocompromised patients: four who had severe infectious diseases and two who had EBV lymphoproliferative disease. All of them underwent multiple safe familial CD45RA- T-cell infusions as adoptive passive cell therapy, containing Cytomegalovirus, Epstein - Barr virus, BK virus, and Aspergillus-specific memory T-cells. We also present the method for selecting the best donors for CD45RA- cells in each case and the procedure to isolate and store these cells. Results: The infusions were safe, there was no case of graft-versus host disease, and they showed a clear clinical benefit. The patients treated for BK virus nephritis, Cytomegalovirus encephalitis, Cytomegalovirus reactivation, and disseminated invasive aspergillosis experienced pathogen clearance, complete resolution of symptoms in 4-6 weeks and a lymphocyte increase in 3 of 4 cases after 3-4 months. Donor T cell transient microchimerism was detected in one patient. The two patients treated for EBV lymphoproliferative disease underwent chemotherapy and several infusions of CD45RA- memory T-cells containing EBV cytotoxic lymphocytes. Donor T-cell microchimerism was observed in both patients. The viremia cleared in one of the patients, and in the other, despite the viremia not clearing, hepatic lymphoproliferative disease remained stable and was ultimately cured with EBV-specific Cytotoxic T-Lymphocytes. Conclusion: The use of familial CD45RA- T-cells containing specific Cytotoxic T-lymphocytes is a feasible, safe and potential effective approach for treating severe pathogen infections in immunocompromised patients through a third party donor. Furthermore, this approach might be of universal use with fewer institutional and regulatory barriers.

Decreased ratio of FOXP3+/FOXP3-CD45RA+CD4+ T cells in peripheral blood is associated with unexplained infertility and ART failure.

Unexplained infertility has a huge social impact and is a significant challenge for both clinicians and researchers. Previous studies have shown the involvement of multiple factors in infertility. Among these, the subset of regulatory T cells is of particular interest for the maternal tolerance towards the semi-allogenic fetus. We investigated circulating CD45RA+ regulatory and non-regulatory CD4+ T cells in healthy women and patients with unexplained infertility in the context of thymic output and peripheral proliferation. The proportion of FOXP3+ and FOXP3-CD45RA+CD4+ T cells in peripheral blood was studied in control groups of healthy parous and nulliparous (never-pregnant) women and in patients with unexplained infertility. In the same groups thymic output and peripheral proliferation were defined by the sj/ßTREC ratio, and signal joint T-cell receptor excision circles (sjTREC) and Ki67 expression, respectively. In parous women a decrease in sjTREC/105 cells and CD45RA+ T lymphocytes, compared to nulliparous group was found. At the same time, the proportion of FOXP3-CD45RA+CD4+ cells, but not FOXP3+CD45RA+ Tregs was reduced. In contrast, in patients with unsuccessful pregnancy, proportions of both regulatory and non-regulatory T cell counterparts were lower. Taken together, our results provide evidence for group-specific properties in the CD45RA+ T cell compartment between healthy parous, nulliparous and women with unexplained infertility.

The Changed Proportion of CD45RA+/CD45RO+ T Cells in Chronic Hepatitis C Patients During Pegylated Interferon-α with Ribavirin Therapy.

Infection with the hepatitis C virus (HCV) may progress toward chronic hepatitis, liver cirrhosis, and liver cancer. A therapy for patients with chronic HCV infection is the combination of pegylated interferon-α with ribavirin, which increases the rate of sustained virological response (SVR) to 56%. However, a practical biomarker to predict SVR is lacking. T cells expressing the CD45RA isoform are considered naive, and antigenic stimulation converts them to CD45RO+. CD45RO+ T cells exhibit immediate response and high lymphokine production, leading to the maintenance and upregulation of immune reactions. The aim of this study is to clarify the proportions of CD45RA+ and CD45RO+ T cells associated with rapid virological response and SVR. We collected blood samples from 32 HCV patients receiving the combined treatment. The samples were collected before, during 4th, 12th, and 24th therapy weeks, and 4th week posttherapy, and their T cell populations were analyzed using flow cytometry. Twenty-nine patients (90.6%) achieved SVR. There were significant declines in proportions of CD45RA+ cells during 4th, 12th, and 24th therapy weeks, and significant increases in proportions of CD45RO+ cells during 24th therapy week and 4th week posttherapy (P < 0.05). Patients undergoing hepatitis C therapy exhibited lowered CD45RA+ cell proportions and increased CD45RO+ cell proportions. This effect may be important in a patient's response to pegylated interferon-α with ribavirin therapy.