Does Maternal Methadone Dose Correlate with Severity of Intrauterine Growth Restriction in Infants with Neonatal Abstinence Syndrome?

Introduction : Previous studies demonstrate a relationship between maternal opioid use during pregnancy and smaller head circumference of infants with neonatal abstinence syndrome (NAS). The goal of this study is to correlate maternal methadone dose and severity of growth restriction in infants with NAS admitted to the neonatal intensive care unit (NICU). Methods: This is a retrospective analysis of infants (≥35 weeks gestation) exposed to in utero methadone, born between August 2006 and May 2018, and admitted to a Philadelphia NICU for medical therapy for NAS. Growth parameters (birth weight, birth length, and birth head circumference) were compared between infants exposed various doses of methadone. The groups were compared using ANOVA, Post-Hoc Tukey, Chi-square and extended Fisher exact tests. Results: A total of 686 infants met the study criteria; 109 in the High dose group, 359 in the Intermediate dose group, and 218 in the Low dose group. There was no significant difference in the use of other drugs or smoking during the pregnancy. Infants exposed to higher doses of methadone displayed significantly smaller head circumferences and lengths at birth. The mean birth weight was similar between the three groups. Discussion: There may be a danger in prescribing high doses of methadone to pregnant mothers, as they may hinder the growth of the infant. We need to conduct more studies investigating how low head circumference and length affect long term developmental outcomes. These findings may help guide physicians toward the optimum dose of methadone for mothers

Peptide extension skews the HA-1 presentation towards activated dendritic cells but reduces the presentation efficiency

Tumorimmunolog

Peptide Length Extension Skews the Minor HA-1 Antigen Presentation toward Activated Dendritic Cells but Reduces Its Presentation Efficiency

Minor histocompatibility Ags (mHags) are important targets of the graft-versus-leukemia effect after HLA-matched allogeneic stem cell transplantation. mHags are HLA-restricted polymorphic peptides expressed on normal and leukemia cells. Vaccination with hematopoiesis-restricted mHag peptides, such as HA-1, may boost the graft-versus-leukemia effect. However, some animal studies indicate that peptides exactly reflecting immunogenic T cell epitopes (short peptides [SPs]) induce tolerance that is potentially due to systemic Ag spreading. Peptide length extension (long peptides [LPs]) may optimize immune responses by restricting and prolonging Ag presentation on dendritic cells (DCs). In this study, we compared the in vitro characteristics and T cell-stimulatory capacities of a human 30-mer HA-1 LP with the 9-mer HA-1 SP. DCs presented the HA-1 LP and SP and expanded HA-1-specific cytotoxic T cell lines. As hypothesized, HA-1 LP presentation, but not SP presentation, was largely restricted to activated DCs and was nearly absent on other hematopoietic cells. However, DCs presented the HA-1 LP 2-3 log levels less efficiently than the SP. Finally, the decay of HA-1 LP and SP presentation on DCs was comparable. We conclude that HA-1 LP and SP differ in their in vitro characteristics and that only comparative clinical studies after allogeneic stem cell transplantation may reveal the optimal HA-1 vaccine. The Journal of Immunology, 2010, 185: 4582-4589.Tumorimmunolog

Targeting a single mismatched minor histocompatibility antigen with tumor-restricted expression eradicates human solid tumors

Regressions of metastatic solid tumors after allogeneic human leukocyte antigen (HLA)-matched stem cell transplantation (SCT) are often associated with detrimental graft-versus-host disease (GVHD). The graft-versus-host reaction of the HLA-matched donor is directed mainly against the multiple mismatched minor histocompatibility antigens (mHags) of the patient. mHags are strong HLA-restricted alloantigens with differential tissue distribution. Ubiquitously expressed mHags are the prime in situ targets of GVHD. The mHag HA-1 is hematopoiesis restricted, but displays additionally an aberrant expression on solid tumors. Thus, HA-1 might be an excellent target to boost the anti-solid tumor effect of allogeneic SCT without inducing severe GVHD. Here, we show that cytotoxic T lymphocytes (CTLs) solely targeting the human mHag HA-1 are capable of eradicating 3-dimensional human solid tumors in a highly mHag-specific manner in vitro, accompanied by interferon-gamma release. In vivo, HA-1-specific CTLs distribute systemically and prevent human breast cancer metastases in immunodeficient mice. Moreover, HA-1-specific CTLs infiltrate and inhibit the progression of fully established metastases. Our study provides the first proof for the efficacy of a clinically applicable concept to exploit single mismatched mHags with hematopoiesis- and solid tumor-restricted expression for boosting the anti-solid tumor effect of allogeneic SCT