Letermovir for Cytomegalovirus prophylaxis in pediatric hematopoietic stem cell transplantation.

BACKGROUND: Letermovir (LTV), an antiviral with exclusive activity against Cytomegalovirus (CMV), is approved for prophylaxis of CMV infection and disease in adult hematopoietic cell transplant (HCT) patients. The use of LTV in the pediatric HCT population is off-label, and has limited literature to support its use. PROCEDURE: This was a single-center, retrospective, matched (1:1 LTV:non-LTV) cohort study of allogeneic HCT recipients transplanted at Children's Hospital Colorado from 2015 to 2022. The primary endpoint was clinically significant CMV DNAemia (defined as a CMV viral load >1000 copies/mL or any CMV DNAemia leading to preemptive treatment) through 6 months post transplant. Secondary outcomes included time to clinically significant CMV DNAemia, drug adverse effects, and dose adjustments of concomitant cyclosporine and voriconazole (known drug interactions). RESULTS: We compared 41 patients who received LTV prophylaxis to 41 patients who received no CMV prophylaxis. There was less clinically significant CMV DNAemia through D+180 in the LTV group (9.8% vs. 17.0%, p = .33). Overall, LTV was well tolerated, and 87.8% of patients experienced no adverse effects related to the drug. There was no observed pattern in LTV effect on cyclosporine serum concentrations, but LTV was associated with decreased voriconazole trough levels. CONCLUSIONS: In this retrospective study, the use of LTV prophylaxis in pediatric stem cell patients was associated with reduced clinically significant CMV DNAemia through D+180.

Health at hand: A systematic review of smart watch uses for health and wellness.

INTRODUCTION: Smart watches have the potential to support health in everyday living by: enabling self-monitoring of personal activity; obtaining feedback based on activity measures; allowing for in-situ surveys to identify patterns of behavior; and supporting bi-directional communication with health care providers and family members. However, smart watches are an emerging technology and research with these devices is at a nascent stage. METHODS: We conducted a systematic review of smart watch studies that engaged people in their use by searching PubMed, Embase, IEEE XPlore and ACM Digital libraries. Participant demographics, device features, watch applications and methods, and technical challenges were abstracted from included studies. RESULTS: Seventy-three studies were returned in the search. Seventeen studies published were included. Included studies were published from 2014 to 2016, with the exception of one published in 2011. Most studies employed the use of consumer-grade smart watches (14/17, 82%). Patient-related studies focused on activity monitoring, heart rate monitoring, speech therapy adherence, diabetes self-management, and detection of seizures, tremors, scratching, eating, and medication-taking behaviors. Most patient-related studies enrolled participants with few exclusion criteria to validate smart watch function (10/17, 58%). Only studies that focused on Parkinson's disease, epilepsy, and diabetes management enrolled persons living with targeted conditions. One study focused on nursing work in the ICU and one focused on CPR training for laypeople. CONCLUSION: Consumer-grade smart watches have penetrated the health research space rapidly since 2014. Smart watch technical function, acceptability, and effectiveness in supporting health must be validated in larger field studies that enroll actual participants living with the conditions these devices target.

Tolerance induction in memory CD4 T cells requires two rounds of antigen-specific activation.

A major goal for immunotherapy is to tolerize the immune cells that coordinate tissue damage in autoimmune and alloantigen responses. CD4 T cells play a central role in many of these conditions and improved antigen-specific regulation or removal of these cells could revolutionize current treatments. A confounding factor is that little is known about whether and how tolerance is induced in memory CD4 T cells. We used MHC class II tetramers to track and analyze a population of endogenous antigen-specific memory CD4 T cells exposed to soluble peptide in the absence of adjuvant. We found that such memory T cells proliferated and reentered the memory pool apparently unperturbed by the incomplete activation signals provided by the peptide. Upon further restimulation in vivo, CD4 memory T cells that had been previously exposed to peptide proliferated, provided help to primary responding B cells, and migrated to inflamed sites. However, these reactivated memory cells failed to survive. The reduction in T-cell number was marked by low expression of the antiapoptotic molecule B cell lymphoma 2 (Bcl2) and increased expression of activated caspase molecules. Consequently, these cells failed to sustain a delayed-type hypersensitivity response. Moreover, following two separate exposures to soluble antigen, no T-cell recall response and no helper activity for B cells could be detected. These results suggest that the induction of tolerance in memory CD4 T cells is possible but that deletion and permanent removal of the antigen-specific T cells requires reactivation following exposure to the tolerogenic antigen.

Influenza nucleoprotein delivered with aluminium salts protects mice from an influenza A virus that expresses an altered nucleoprotein sequence.

Influenza virus poses a difficult challenge for protective immunity. This virus is adept at altering its surface proteins, the proteins that are the targets of neutralizing antibody. Consequently, each year a new vaccine must be developed to combat the current recirculating strains. A universal influenza vaccine that primes specific memory cells that recognise conserved parts of the virus could prove to be effective against both annual influenza variants and newly emergent potentially pandemic strains. Such a vaccine will have to contain a safe and effective adjuvant that can be used in individuals of all ages. We examine protection from viral challenge in mice vaccinated with the nucleoprotein from the PR8 strain of influenza A, a protein that is highly conserved across viral subtypes. Vaccination with nucleoprotein delivered with a universally used and safe adjuvant, composed of insoluble aluminium salts, provides protection against viruses that either express the same or an altered version of nucleoprotein. This protection correlated with the presence of nucleoprotein specific CD8 T cells in the lungs of infected animals at early time points after infection. In contrast, immunization with NP delivered with alum and the detoxified LPS adjuvant, monophosphoryl lipid A, provided some protection to the homologous viral strain but no protection against infection by influenza expressing a variant nucleoprotein. Together, these data point towards a vaccine solution for all influenza A subtypes.

The Ikaros transcription factor regulates responsiveness to IL-12 and expression of IL-2 receptor alpha in mature, activated CD8 T cells.

The Ikaros family of transcription factors is critical for normal T cell development while limiting malignant transformation. Mature CD8 T cells express multiple Ikaros family members, yet little is known about their function in this context. To test the functions of this gene family, we used retroviral transduction to express a naturally occurring, dominant negative (DN) isoform of Ikaros in activated CD8 T cells. Notably, expression of DN Ikaros profoundly enhanced the competitive advantage of activated CD8 T cells cultured in IL-12, such that by 6 days of culture, DN Ikaros-transduced cells were 100-fold more abundant than control cells. Expression of a DN isoform of Helios, a related Ikaros-family transcription factor, conferred a similar advantage to transduced cells in IL-12. While DN Ikaros-transduced cells had higher expression of the IL-2 receptor alpha chain, DN Ikaros-transduced cells achieved their competitive advantage through an IL-2 independent mechanism. Finally, the competitive advantage of DN Ikaros-transduced cells was manifested in vivo, following adoptive transfer of transduced cells. These data identify the Ikaros family of transcription factors as regulators of cytokine responsiveness in activated CD8 T cells, and suggest a role for this family in influencing effector and memory CD8 T cell differentiation.

Vaccine adjuvants aluminum and monophosphoryl lipid A provide distinct signals to generate protective cytotoxic memory CD8 T cells.

Vaccines can greatly reduce the spread of and deaths from many infectious diseases. However, many infections have no successful vaccines. Better understanding of the generation of protective CD8 memory T cells by vaccination is essential for the rational design of new vaccines that aim to prime cellular immune responses. Here we demonstrate that the combination of two adjuvants that are currently licensed for use in humans can be used to prime long-lived memory CD8 T cells that protect mice from viral challenge. The universally used adjuvant, aluminum salts, primed long-lived memory CD8 T cells; however, effective cytotoxic T-cell differentiation occurred only in the presence of an additional adjuvant, monophosphoryl lipid A (MPL). MPL-induced IL-6 was required for cytotoxic differentiation. The IL-6 acted by inducing granzyme B production and reducing expression of inhibitory molecule PD1 on the surface of the primed CD8 T cells. CD8 memory T cells generated by antigen delivered with both aluminum salts and MPL provided significant protection from influenza A challenge. These adjuvants could be used in human vaccines to prime protective memory CD8 T cells.

Memory CD4 T cells that express CXCR5 provide accelerated help to B cells.

CD4 T cell help for B cells is critical for effective Ab responses. Although many of the molecules involved in helper functions of naive CD4 T cells have been characterized, much less is known about the helper capabilities of memory CD4 T cells, an important consideration for the design of vaccines that aim to prime protective memory CD4 T cells. In this study, we demonstrate that memory CD4 T cells enable B cells to expand more rapidly and class switch earlier than do primary responding CD4 T cells. This accelerated response does not require large numbers of memory cells, and similar numbers of primary responding cells provide less effective help than do memory cells. However, only memory CD4 T cells that express the B cell follicle homing molecule, CXCR5, are able to accelerate the response, suggesting that the rapidity of the Ab response depends on the ability of CD4 memory T cells to migrate quickly toward B cells.