Phase I dose-escalation single centre clinical trial to evaluate the safety of infusion of memory T cells as adoptive therapy in COVID-19 (RELEASE).

BACKGROUND: Effective treatments are still needed to reduce the severity of symptoms, time of hospitalization, and mortality of COVID-19. SARS-CoV-2 specific memory T-lymphocytes obtained from convalescent donors recovered can be used as passive cell immunotherapy. METHODS: Between September and November 2020 a phase 1, dose-escalation, single centre clinical trial was conducted to evaluate the safety and feasibility of the infusion of CD45RA- memory T cells containing SARS-CoV-2 specific T cells as adoptive cell therapy against moderate/severe cases of COVID-19. Nine participants with pneumonia and/or lymphopenia and with at least one human leukocyte antigen (HLA) match with the donor were infused. The first three subjects received the lowest dose (1 × 105 cells/kg), the next three received the intermediate dose (5 × 105 cells/kg) and the last three received the highest dose (1 × 106 cells/kg) of CD45RA- memory T cells. Clinicaltrials.gov registration: NCT04578210. FINDINGS: All participants' clinical status measured by National Early Warning Score (NEWS) and 7-category point ordinal scales showed improvement six days after infusion. No serious adverse events were reported. Inflammatory parameters were stabilised post-infusion and the participants showed lymphocyte recovery two weeks after the procedure. Donor microchimerism was observed at least for three weeks after infusion in all patients. INTERPRETATION: This study provides preliminary evidence supporting the idea that treatment of COVID-19 patients with moderate/severe symptoms using convalescent CD45RA- memory T cells is feasible and safe. FUNDING: Clinical Trial supported by Spanish Clinical Research Network PT17/0017/0013. Co-funded by European Regional Development Fund/European Social Fund. CRIS CANCER Foundation Grant to AP-M and Agencia Valenciana de Innovación Grant AVI-GVA COVID-19-68 to BS.

Month of birth, HLA-DRB1*15 locus and risk of multiple sclerosis in offspring. / Mes de nacimiento, HLA-DRB1 y riesgo de esclerosis multiple en la descendencia.

INTRODUCTION: A relationship among April births, HLA-DRB1*15:01 genotype and risk of multiple sclerosis (MS) has been described. We aim to determine this association in our cohort of Spanish MS patients. SUBJECTS AND METHODS: We genotyped HLA-DRB1*15:01 allele in 326 MS patients and 226 controls (non-neurological disease patients) by SSP-PCR and compared month of birth with local births during the same period. RESULTS: MS patients carrying HLA-DRB1*15 allele were more frequently born in December (10.3% HLA-DRB1*15+ vs. 3.8% HLA-DRB1*15-; p = 0.019). Controls carrying HLA-DRB1*15 allele were less frequently born in December than non-carrier controls (0% HLA-DRB1*15+ vs. 10.3% HLA-DRB1*15-; p = 0.028). Thus, December was confirmed as the common month of birth for HLA-DRB1*15-non-carrier controls and MS HLA-DRB1*15-carrier patients. CONCLUSIONS: Month of birth, HLA-DRB1 genotype and risk of MS are associated. In Spain, this association was found in December, supporting the potential interaction of a seasonal risk factor in winter, inside/close to HLA-DRB1*15 locus, during pregnancy or after birth.

TITLE: Mes de nacimiento, HLA-DRB1 y riesgo de esclerosis multiple en la descendencia.Introduccion. El haplotipo HLA-DRB1*1501 es el marcador genetico que se ha asociado con un riesgo tres veces mayor de padecer esclerosis multiple (EM) en caucasicos occidentales. Recientemente se ha sabido que hay una asociacion entre el mes de nacimiento en abril, el genotipo HLA-DRB1 y el riesgo de EM en paises del norte de Europa y Canada. Esto apoya la teoria de que debe haber una interaccion entre un factor de riesgo estacional con un locus cercano al HLA-DRB1*15 durante la gestacion o cerca del posparto. Sujetos y metodos. Se realizo el genotipado de la presencia y subtipo de HLA-DRB1*1501 en 326 pacientes de dos centros espa˜oles y en 226 controles sin patologia neurologica. Se compararon los meses de nacimiento de la muestra de pacientes con los nacimientos mensuales locales en los mismos periodos. Resultados. Comparados los pacientes con EM que eran portadores del alelo HLA-DRB1*15 (10,3%) frente a los pacientes no portadores (3,8%), significativamente mas pacientes nacian en diciembre (p = 0,0185). Tambien se confirmaba el mismo mes de nacimiento de diciembre entre sanos portadores frente a no portadores de HLA-DRB1*15 y entre pacientes portadores de HLA-DRB1*15 frente a sanos. Conclusiones. El mes de nacimiento, el genotipo HLA-DRB1*15 y el riesgo de presentar EM estan asociados. A diferencia de los resultados obtenidos en paises del norte de Europa, donde esta asociacion se ha encontrado en el mes de abril, en Espa˜a es en diciembre. Se demuestra la interaccion de un factor de riesgo estacional en invierno en el locus HLA-DRB1*15 o cercano a este durante la gestacion o tras el nacimiento.