Sunhee Hwang

Microscopic nodes and ducts inside lymphatics and on the surface of internal organs are rich in granulocytes and secretory granules

The blood and lymphatic systems are the two well-established circulatory systems. The existence of a third circulatory system representing acupuncture meridians was claimed in the 1960s. The very existence and function of the system, however, remained uncertain. We have found that microscopic nodes and ducts inside lymphatics, as well as on the surface of internal organs of the rat. The nodes and ducts are covered by a layer of EMP-3-positive spindle-shaped epithelium with, below, a layer of vWF-positive but CD31-negative endothelium. The nodes contain a variety of immune cells, usually enriched with mast cells, eosinophils, neutrophils and histiocytes, as well as chromaffin cells, other granule-containing cells. Secretory granules originating from the mast cells in the nodes appear to pass along ductules, two or more of which make up a duct. Our results reveal a potential circulatory system whose anatomical structure and cellular content differ from the blood and lymph systems, and which may be involved in the transport of secretory granules.

4-1BB Signaling Enhances Primary and Secondary Population Expansion of CD8+ T Cells by Maximizing Autocrine IL-2/IL-2 Receptor Signaling.

4-1BB (CD137), a member of the tumor necrosis factor receptor superfamily (TNFRSF), is primarily expressed on activated T cells and is known to enhance proliferation of T cells, prevent activation-induced cell death, and promote memory formation of CD8+ T cells. In particular, it is well acknowledged that 4-1BB triggering preferentially enhances the expansion of CD8+ T cells rather than CD4+ T cells, but the underlying mechanism remains unclear. Here we found that 4-1BB triggering markedly increased IL-2Rα (CD25) and IL-2 expressions of CD8+ T cells but minimally for CD4+ T cells. Proliferation of CD8+ T cells was moderately enhanced by direct 4-1BB triggering in the absence of signaling through IL-2Rα/IL-2 interactions, but further promoted in the presence of IL-2Rα/IL-2 interactions. Among the TNFRSF members including OX40, GITR, CD30, and CD27, 4-1BB was superior in the ability to induce IL-2Rα expression on CD8+ T cells. When the primary and secondary expansions of CD8+ T cells in vivo were examined by adoptively transferring OVA-specific CD8+ T cells along with the treatment with agonistic anti-4-1BB and/or antagonistic anti-CD25 F(ab’)2 mAb, 4-1BB triggering enhanced both primary and secondary expansion of CD8+ T cells in vivo, and the 4-1BB effects were moderately suppressed in primary expansion while completely abolished in secondary expansion of OVA-specific CD8+ T cells by blocking IL-2Rα. These results suggest that 4-1BB-mediated increases of IL-2Rα and IL-2 prolong the effects of transient TCR- and 4-1BB-mediated signaling in CD8+ T cells, and that 4-1BB triggering preferentially enhances the expansion of CD8+ T cells through the amplification of autocrine IL-2/IL-2R signaling loop.

Nonmarrow hematopoiesis occurs in a hyaluronic-acid-rich node and duct system in mice.

A hyaluronic-acid-rich node and duct system (HAR-NDS) was found on the surface of internal organs of mice, and inside their blood and lymph vessels. The nodes (HAR-Ns) were filled with immune cells of the innate system and were especially enriched with mast cells and histiocytes. They also contained hematopoietic progenitor cells (HPCs), such as granulocyte-macrophage, erythroid, multipotential progenitors, and mast cell progenitors (MCPs). MCPs were the most abundant among the HPCs in HAR-Ns. Their frequency was fivefold higher than that of the MCPs in bone marrow. In addition, the system contained pluripotent stem cells (PSCs) capable of producing CD45(-)Flk1(+) hemangioblast-like cells, which subsequently generated various types of HPCs and differentiated blood cells. Although HAR-Ns did not appear to harbor enough number of cells capable of long-term reconstitution or short-term radioprotection of lethally irradiated recipients, bone marrow cells were able to engraft in the HAR-NDS and reconstitute hematopoietic potentials of the system. PSCs and HPCs were consistently found in intravenous, intralymphatic, and intestinal HAR-ND. We infer that PSCs and HPCs reside in the HAR-ND and that this novel system may serve as an alternative means to traffic immature and mature blood cells throughout the body.

Novel HLA-Cw*01 allele, Cw*010203, identified by sequence-based typing*

In this report, we describe the identification of an human leucocyte antigen-Cw*0102 (HLA-Cw*0102) nucleotide sequence variant, a new HLA-Cw*010203, in a case - control study by using sequence-based typing. Allele HLA-Cw*010203 showed one nucleotide difference with HLA-Cw*010201 by a silent substitution at codon 130 (CTG-->CTA).

Effect of Hydroxyethyl Starch on Acute Kidney Injury After Living Donor Hepatectomy.

BACKGROUND Concerns about the adverse effects of hydroxyethyl starch (HES) on renal function have been raised in recent studies involving critically ill patients. We aimed to evaluate the effect of HES on acute kidney injury (AKI) after living donor right hepatectomy. METHODS We performed a 1:3 propensity score matching analysis of the medical records of 1641 living donors who underwent a donor right hepatectomy. They were divided into the control group (n = 60), who received only crystalloids, and the colloid group (n = 1,581), who received HES 130/0.4 and crystalloids. Postoperative AKI was determined by AKI Network (AKIN) and Risk, Injury, Failure, Loss, End-stage (RIFLE) criteria. RESULTS A 1:3 propensity score matching was performed in 206 donors, 54 donors in the control group and 152 donors in the colloid group. For the matched colloid group, the median amount of 7.65 mL/kg (interquartile range, 6.64-9.20) of colloid and 58.19 mL/kg (interquartile range, 45.63-71.51) of crystalloid were given. The median amount of administered crystalloid in the control group was 56.48 mL/kg (interquartile range, 47.94-76.12) after propensity score matching. The incidences of AKI were not different between the control and colloid groups (P = .460 by AKIN criteria; P = .999 by RIFLE criteria). CONCLUSION Intraoperative administration of HES may not be associated with AKI after living donor hepatectomy. This result can provide useful information on perioperative fluid management in living liver donors.

Selective killing of malignant B cells using T cells redirected against malignancy variant receptor

Background Advances in gene-transfer system and in-depth understanding of immune mechanism have made the immunotherapy a powerful tool for fighting against cancers. Recent studies demonstrated a therapeutic potential of T cells with chimeric antigen receptor (CAR) targeting CD19 in refractory hematopoietic malignancies. At the same time, however, hence the CD19 targeting results in normal cell destruction such as B cell aplasia, a novel marker that specifically expressed in malignant B cells should be applied. In this study, we developed anti-malignancy variant receptor (MVR) mAb that exclusively bound to malignant B cells but not to normal B cells, and demonstrated that autologous T cells expressing CAR construct with anti-MVR scFv (MVR-CAR T cells) efficiently suppressed the outgrowth of malignant B cells in lymphoid organs.

Desensitized chimeric antigen receptor T cells selectively recognize target cells with enhanced antigen expression

Chimeric antigen receptor (CAR) T cell therapy is an effective method for treating specific cancers. CARs are normally designed to recognize antigens, which are highly expressed on malignant cells but not on T cells. However, when T cells are engineered with CARs that recognize antigens expressed on the T cell surface, CAR T cells exhibit effector function on other T cells, which results in fratricide, or killing of neighboring T cells. Here, using human leukocyte antigen-DR (HLA-DR)-targeted CAR T cells, we show that weak affinity between CAR and HLA-DR reduces fratricide and induces sustained CAR downregulation, which consequently tunes the avidity of CAR T cells, leading to desensitization. We further demonstrate that desensitized CAR T cells selectively kill Epstein-Barr virus-transformed B cells with enhanced HLA-DR expression, while sparing normal B cells. Our study supports an avidity-tuning strategy that permits sensing of antigen levels by CAR T cells.Engineered T cells with chimeric antigen receptor (CAR) are emerging as an effective cancer therapy. Here the authors show that CAR T cells recognizing self-MHC can be ‘tuned’ ex vivo via CAR downregulation and CAR T cell death to generate a CAR T pool specifically targeting tumor cells with high MHC expression.