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Background Thymic-derived regulatory T cells (tTreg) are critical regulators of the immune system. Adoptive tTreg transfer is a curative therapy for murine models of autoimmunity, graft rejection, and graft versus host disease (GVHD). We previously completed a “first-in-human” clinical trial using in vitro expanded umbilical cord blood (UCB) derived tTreg to prevent GVHD in patients undergoing UCB hematopoietic stem cell transplantation (HSCT). tTreg were safe and demonstrated clinical efficacy, but low yield prevented further dose escalation. Methods To optimize yield, we investigated the use of KT64/86 artificial antigen presenting cells (aAPC) to expand tTreg and incorporated a single re-stimulation after day 12 in expansion culture. Results aAPC increased UCB tTreg expansion >8-fold over CD3/28 stimulation. Re-stimulation with aAPC increased UCB tTreg expansion an additional 20–30 fold. Re-stimulated human UCB tTreg ameliorated GVHD disease in a xenogeneic model. Following cGMP validation, a trial was conducted with tTreg. tTreg doses up to >30-fold higher compared to that obtained with anti-CD3/28 mAb coated-bead expansion and Foxp3 expression was stable during in vitro expansion and following transfer to patients. Increased expansion did not result in a senescent phenotype and GVHD was significantly reduced. Discussion Expansion culture with cGMP aAPC and re-stimulation reproducibly generates sufficient numbers of UCB tTreg that exceeds the numbers of T effector cells in an UCB graft. The methodology supports future tTreg banking and is adaptable to tTreg expansion from HSC sources. Furthermore, since HLA matching is not required, allogeneic UCB tTreg may be a useful strategy for prevention of organ rejection and autoimmune disease.

We have shown previously that cytokines IL-4 and IL-13 induce protection in porcine vascular endothelial cells (EC) against killing by the membrane attack complex (MAC) of human complement. This protection is intrinsic, not due to changes in complement regulatory proteins, and requires activation of Akt and sterol receptor element binding protein-1 (SREBP-1), which regulates fatty acid and phospholipid synthesis. Here we report that, compared to EC incubated in medium, IL-4-treated EC had a profound reduction in complement-mediated ATP loss and in killing assessed by vital dye uptake, but only a slight reduction in permeability disruption measured by calcein release. While controls exposed to complement lost mitochondrial membrane potential and subsequently died, protected EC maintained mitochondrial morphology and membrane potential, and remained alive. SREBP-1 and fatty acid synthase activation were required for protection and fatty acid and phospholipid synthesis, including cardiolipin, were increased after IL-4 stimulation, without increase in cholesterol content or cell proliferation. IL-4 also induced protection of EC from killing by the channel forming protein melittin, similar to protection observed for the MAC. We conclude that IL-4 induced activation of Akt/SREBP-1/lipid biosynthesis in EC, resulting in protection against MAC and melittin, in association with mitochondrial protection. IntroductionThe vascular endothelium has critically important physiologic functions [1] and, if injured, pathologic states such as atherosclerosis, ischemia reperfusion, and vasculopathy, as observed in vascularized allo-and xenograft rejection, may result. The vascular endothelium is directly exposed to complement, complement activation may take place in blood secondary to various physiologic and pathologic events, and activated complement may influence vascular endothelial physiology [2,3]. Among products derived from complement activation, the membrane attack complex (MAC) of human complement is known to have multiple effects on the vascular endothelium and the vasculature as a whole, including activation, production of inflammatory cytokines, expression of adhesion molecules, loss of endothelial anticoagulant properties, gain of procoagulant properties, cell retraction and detachment from the basement membrane, and cell death [2,3]. Consequently, the MAC may initiate or contribute to ischemia or to acute and chronic inflammation, becoming a major pathophysiologic mediator in vascular diseases, autoimmune diseases, and graft rejection. Cells possess at least three control mechanisms for protection against injury from the MAC. First, the membrane proteins decayaccelerating factor (CD55) and membrane cofactor protein (CD46) inhibit progression of complement activation at the C3 and C5 activation stages, and CD59 inhibits MAC assembly by blocking C9 binding to C5b-8 [4]. Second, complement proteins bound to a cell membrane may be removed from the membrane by exocytosis or endocytosis [5]. Third, nucleated cells may be in...

Erdheim-Chester disease (ECD) is a rare form of systemic histiocytosis, typically presenting with striking osseous involvement characterized by bilateral osteosclerosis and involvement of organs such as the lung, pituitary gland, heart, and brain. Liver involvement with ECD is extremely uncommon. We report a 56-year-old woman presenting with newly diagnosed cirrhosis and signs concerning for intra-abdominal malignancy, including omental caking and peritoneal thickening. Liver biopsy demonstrated xanthogranulomatous infiltration from ECD. The patient showed initial improvement with interferon therapy, but she developed severe depression, which led to the discontinuation of the treatment. Shortly afterward, she died from progressive liver dysfunction resulting in hepatorenal syndrome.

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Actinic prurigo (AP) is a chronic idiopathic photodermatosis that primarily affects American Indians in the United States and Mestizos in Latin American countries. Clinically, the onset of the disease is usually in the first decade of life but may appear initially in adult life, and it is characterized by symmetric involvement of sun-exposed areas of the skin, particularly areas of the face, resulting in polymorphic erythematous papules, macules, and plaques in different stages of evolution. Lower lip involvement includes swelling, scaling, fissures, hyperpigmentation, and ulcerations of the vermilion border. and in some cases could represent the only manifestation of the disease. The histopathologic features of AP have been studied; however, there is a controversy regarding whether AP cheilitis has distinct histopathologic features that could allow accurate separation from other specific and nonspecific forms of cheilitis. The diagnosis can be challenging, mainly when lip lesions are the only manifestation of the disease. In this study, the authors investigate the clinicopathologic features of 75 cases of AP cheilitis to provide further criteria for its diagnosis and classification. All 75 patients presented with lip lesions. Thirty-three cases were diagnosed as AP cheilitis with cutaneous lesions and 42 cases were diagnosed as AP cheilitis without cutaneous lesions (only lip lesions). Histologically, of the 33 cases with AP cheilitis with cutaneous lesions, 17 (52%) cases showed follicular cheilitis, and of the 42 cases that had only lip lesions, 18 (43%) cases showed follicular cheilitis. Histologically, AP cheilitis can present as follicular cheilitis; thus, supporting the diagnosis. Also, our findings confirm that lip lesions can present as the only manifestation of the disease, showing typical histological and clinical features. This form of cheilitis has not being well described in the dermatologic and dermatopathologic literature.

Posttransplant lymphoproliferative disorder (PTLD) is a known complication of solid organ transplantation. Diffuse large B-cell lymphoma (DLBCL) is frequently seen in this setting. However, CD30+ DLBCL with sinusoidal pattern of involvement has not been reported in pediatric PTLD. We are reporting a 9-year-old female child presented with diffuse lymphadenopathy postheart transplantation. The pattern of involvement was suggestive of anaplastic large cell lymphoma, but the malignant cells were positive for B-cell markers and negative for anaplastic lymphoma kinase. The patient was treated aggressively with multiagent chemotherapy and rituximab. Accurate diagnosis in PTLD is paramount in making management decisions.

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