Hyun-Sil Park

Grape seed proanthocyanidin extract (GSPE) differentially regulates Foxp3 + regulatory and IL-17 + pathogenic T cell in autoimmune arthritis

Grape seed proanthocyanidin extract (GSPE), which is the antioxidant derived from grape seeds, has been reported to possess a variety of potent properties. We have previously shown that GSPE attenuates collagen-induced arthritis. However the mechanism by which GSPE regulates the immune response remains unclear, although it may involve effects on the regulation of pathogenic T cells in autoimmune arthritis. To clarify this issue, we have assessed the effects of GSPE on differential regulation of Th17 and regulatory T (Treg) cells subsets in vitro in mouse and human CD4(+) T cells. We observed that GSPE decreased the frequency of IL-17(+)CD4(+)Th17 cells and increased induction of CD4(+)CD25(+)forkhead box protein 3 (Foxp3)(+) Treg cells. In vivo, GSPE effectively attenuated clinical symptoms of established collagen-induced arthritis in mice with concomitant suppression of IL-17 production and enhancement of Foxp3 expression (type II collagen-reactive Treg cells) in CD4(+) T cells of joints and splenocytes. The presence of GSPE decreased the levels of IL-21, IL-22, IL-26 and IL-17 production by human CD4(+) T cells in a STAT3-dependent manner. In contrast, GSPE induces Foxp3(+) Treg cells in humans. Our results suggest that GSPE possesses a reciprocal control over IL-17 and Foxp3. By potently regulating inflammatory T cell differentiation, GSPE may serve as a possible novel therapeutic agent for inflammatory and autoimmune diseases, including rheumatoid arthritis.

IL-17-deficient allogeneic bone marrow transplantation prevents the induction of collagen-induced arthritis in DBA/1J mice

IL-17-producing CD4+ T cells (Th17) play important functions in autoimmune diseases and allograft rejection of solid organs. We examined the effects of IL 17 and its mechanism of action on arthritis in a murine collagen-induced arthritis (CIA) model using bone marrow transplantation (BMT) system. DBA/1J mice were administered a lethal radiation dose and then rescued with bone marrow derived from either wild-type (WT) or IL-17-/- mice on C57BL/6 background mice. CIA was induced after the bone marrow transplant, and disease progression was characterized. DBA/1J mice with CIA that received IL-17-/- donor bone marrow showed potently inhibited development and severity of clinical arthritis as compared with CIA mice that received WT bone marrow. Reduced secretion of the pro-inflammatory cytokines tumor necrosis factor-α, IL-1β, and IL-6, and collagen-specific T cell responses were observed in mice that received IL-17-/- bone marrow. IL-17 blockade also inhibited effector T cell proliferation by reciprocally regulating the Treg/Th17 ratio. IL-17 blockade prevented joint destruction in mice with CIA. These findings suggest that CIA with BMT is a viable method of immunological manipulation and that IL-17 deficiency suppresses severe joint destruction and inflammation in CIA mice. There may be clinical benefits in blocking IL-17 and BMT in the treatment of rheumatoid arthritis.

Induction of Mixed Chimerism Using Combinatory Cell-Based Immune Modulation with Mesenchymal Stem Cells and Regulatory T Cells for Solid-Organ Transplant Tolerance

Establishment of mixed chimerism is an ideal approach to induce donor-specific tolerance while expanding its potential in various clinical settings. Despite the developments in partial conditioning regimens, improvements are still needed in reducing toxicity and bone marrow transplantation-related complications. Recently, cell-based therapies, including mesenchymal stem cells (MSCs), have been incorporated in establishing noncytoreductive mixed chimerism protocols; however, its efficacy is only partial and shows reversed immunosuppressive properties. This study demonstrates a novel approach to induce mixed chimerism and tolerance through combinatory cell-based immune modulation (CCIM) of MSCs and regulatory T cells (Tregs). We hypothesize that the interaction between these cells may lead to greater inhibition of host immune responses. Compared with single cell therapy, CCIM induced a higher engraftment rate and robust donor-specific tolerance to skin allografts across full major histocompatibility complex barriers. These regulatory effects were associated with inhibition of natural killer cell cytotoxic activity, CD4(+)IL-17(+) cells, memory B cells, plasma cells, and immunoglobulin production levels along with increased frequencies of CD4(+)Foxp3(+) cells, IL-10-producing mature B cells, and myeloid-derived suppressor cells. Furthermore, CCIM was able to regulate mortality in a graft-versus-host disease model through reciprocal regulation of Treg/Th17. Taken together, we suggest CCIM as a clinically applicable strategy for facilitating the induction of mixed chimerism and permanent tolerance.

The antimicrobial peptide human cationic antimicrobial protein‐18/cathelicidin LL‐37 as a putative growth factor for malignant melanoma

Background  Recent evidence suggests cathelicidin LL‐37 to be a growth factor for various human cancers such as lung cancer, ovarian cancer and breast cancer. However, the effect of LL‐37 against malignant skin cancer has not been reported.

Adoptive transfer of all-trans-retinal-induced regulatory T cells ameliorates experimental autoimmune arthritis in an interferon-gamma knockout model.

Maintaining an appropriate balance between subsets of CD4+ helper T cells and T regulatory cells (Tregs) is a critical process in immune homeostasis and a protective mechanism against autoimmunity and inflammation. To identify the role of vitamin A-related compounds, we investigated the regulation of interleukin (IL)-17-producing helper T cells (Th17 cells) and Tregs treated with all-trans-retinal (retinal). CD4+T cells or total cells from the spleens of C57BL/6 mice were stimulated under Treg-polarizing (anti-CD3/CD28 and TGF-β) or Th17-polarizing (anti-CD3/CD28, TGF-β, and IL-6) conditions in the presence or absence of retinal. To analyze their suppressive abilities, retinal-induced Tregs or TGF-β-induced Tregs were co-cultured with responder T cells. Collagen-induced arthritis (CIA) was established in interferon (IFN)-γ knockout mice. On day 13, retinal-induced Tregs were adoptively transferred to mice with established CIA after second immunizations. Compared with TGF-β-induced Treg cells, retinal-induced Tregs showed increased Foxp3 expression and mediated stronger suppressive activity. Under Th17-polarizing conditions, retinal inhibited the production of IL-17 and increased the expression of Foxp3.Retinal-induced Tregs showed therapeutic effects in IFN-γ knockout CIA mice. Thus, we demonstrated that retinal reciprocally regulates Foxp3+ Tregs and Th17 cells. These findings suggest that retinal, a vitamin A metabolite, can regulate the balance between pro- and anti-inflammatory immunity. A better understanding of the manipulation of Foxp3 and Tregs may enable the application of this tremendous therapeutic potential in various autoimmune diseases.

A case of idiopathic leuconychia totalis and partialis

SIR, Leuconychia is the most common chromatic disorder of the nail and is classified as pseudoleuconychia resulting from nail plate alteration due to an external origin, apparent leuconychia resulting from subungual and nail bed abnormalities, and true leuconychia where nail plate abnormalities originate in the nail matrix. True leuconychia includes four distinct categories according to distribution of white colour: leuconychia punctata, leuconychia striata, leuconychia partialis and leuconychia totalis. Most cases of true leuconychia may be congenital or, if acquired, may be associated with underlying systemic diseases such as typhoid fever, hepatic cirrhosis, ulcerative colitis or leprosy, and may also be associated with local trauma of the nail matrix, use of emetine, cytostatic agents or local exposure to salty solutions. Idiopathic true leuconychia is a very rare condition and only a few previous reports have described the findings in the progression from leuconychia partialis to leuconychia totalis. We report a 26-year-old man who presented with idiopathic leuconychia which demonstrated a progression from leuconychia partialis to combined leuconychia totalis and partialis. He had had asymptomatic white fingernails for 13 years, affecting the digits on both hands with the exception of the left thumb, with no family history of white fingernails (Fig. 1a). On examination, he had no hair, teeth or skin abnormalities. Leuconychia partialis was seen on the right thumb, left ring finger and both little fingers, with distal transverse white bands. The other fingers showed leuconychia totalis except for the left thumb nail, which showed yellow spikes unlike the other white fingernails. No toenail was involved. Pitting, splitting or ridging of the fingernails was not seen, and there was no subungual hyperkeratosis. Texture, shape and hardness were also normal. He denied taking any medication and having any other systemic illness. He also had experienced no specific trauma and no chemical exposures to his fingers or fingernails. According to the patient, he had had this condition for 13 years, during which period the whitening of the fingernails had progressed slowly. Repeated potassium hydroxide preparations and fungal cultures of the white nails were negative except for the left thumb nail. Potassium hydroxide preparation was positive at the left thumb nail and Trichophyton rubrum was cultured. Laboratory studies including full blood count, urinalysis, liver function tests, renal function tests, total protein, albumin, erythrocyte sedimentation rate and C-reactive protein were normal or negative. Microscopic examination of a white nail plate revealed a globular collection of large immature keratohyaline granules (Fig. 1b), whereas biopsy specimens from the nail bed and nail matrix were unremarkable. Interestingly, our patient also had onychomycosis of the left thumb, for which we prescribed itraconazole pulse therapy (two pulses of 400 mg daily for 7 days). Although no treatment is indicated or available for true leuconychia, we gave intralesional injections of corticosteroid (triamcinolone acetonide 5 mg mL at 1–2-week intervals) into the proximal nail fold for cosmetic reasons. Because true leuconychia is thought to be due to abnormal matrix keratinization, with persistence of keratohyaline granules in the nail plate, we considered that corticosteroid treatment might help to make these cells differentiate. After 2 months of treatment, the left thumb nail was somewhat improved, but the other fingernails showed no visible change. Our patient has shown persistence and ⁄or a slight progression in his nail whitening during 2 years of follow-up. b a

A novel influenza a (H1N1) virus as a possible cause of pityriasis rosea

Editor A 6-year-old-girl was seen in consultation for an erythematous papulosquamous eruption on the trunk (Fig. 1). Six days prior to visit, she had been ill with influenza-like illness for four days. She was admitted to the children’s hospital emergency department. Screened for the novel influenza A virus, which revealed positive H1N1 status. The patient was treated with oseltamivir therapy. Additionally, the result of polymerase chain reaction (PCR) of nasopharyngeal secretion was positive for H1N1 virus. At a 2-day follow-up appointment, she was referred to our department. Upon physical examination, an ovoid erythematous scaly patch with a 2–3-cm diameterand multiple smaller lesions were noted on the back (in a ‘Christmas tree’ pattern) (Fig. 2). The patient was otherwise in good health. According to parent, the skin lesions began with a solitary patch ten days earlier and the generalized eruption with high fever followed 4 days later. The rash failed to respond to topical corticosteroid cream. One week later, a skin biopsy from the largest patch was performed. The clinical appearance of the rash and the microscopic descriptions were consistent with a diagnosis of PR, but the virus was not detected in her skin tissue. At one month follow-up, the rash resolved spontaneously. PR is erythematous-squamous lesions of the trunk and limbs. Although the exact cause of PR is not clear, it has been suspected to be associated with infection because of ‘outbreaks’ of PR among certain groups. Additionally, epidemiological data suggest that various viruses may be causative agents for PR. However, critical evaluation of the medical literature on PR does not reveal credible evidence that PR may be associated with any pathogen other than HHV-7 and HHV-6. In April 2009, a novel influenza A virus was identified in Mexico and has since spread worldwide. However, cutaneous complications of the novel influenza A infection have not been well described. In our case, PCR of nasopharyngeal secretion was positive for H1N1 virus but not in the sample of skin tissue. We suggest three possible scenarios (referred to as ‘A’ and ‘B’ and ‘C’) for the negative result of skin tissue: (A) Neurological complications of seasonal influenza virus infection have been well described. However, virus was not found in CSF samples or recovered tissue samples. This suggests that the neurological manifestations are related to inflammatory responses with increase in cytokine release. Like the neurological complications, several studies focused on the immune response against viruses proposed as causative agents for PR. (B) Generally, the influenza A virus does not infect epithelial cells or cause large viral loads within skin lesions, which explains the difficulty in detecting these viruses by electron microscopy and by PCR

Interleukin 21 blockade modulates activated T- and B-cell homeostasis via B-cell activating factor pathway-mediated inhibition in a murine model of acute graft-versus-host disease.

Interleukin (IL) 21 plays a key role in the development of acute graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation. Therapeutic manipulation of IL-21 activity may improve acute GVHD during the early-posttransplant period. We investigated the mechanisms regulating T- and B-cells during IL-21 blockade in acute GVHD. Interleukin 21 blockade enhanced regulatory T and T helper (Th) 2 cell differentiation and inhibited Th1- and Th17-derived transcription factors and cytokines as a modulator of activated T-cells. Interleukin 21(-/-) cell recipients showed increased mature B- and marginal-zone B-cells, but decreased memory B-cells, germinal center formation, and plasma cells that did not lead to immunoglobulin production. B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) are involved in the induction and maintenance of T- and B-cell responses. We observed decreased levels of only BAFF during acute GVHD and confirmed that mammalian target of rapamycin complex 1 was reduced by the BAFF/BAFF-receptor pathway. Therefore, this study suggests that IL-21 blockade modulates activated T- and B-cell homeostasis via BAFF-pathway-mediated inhibition in acute GVHD following murine allogeneic bone marrow transplantation.

An unusual terminal hair growth on the nose tip associated with gefitinib therapy

SIR, The epidermal growth factor receptor (EGFR) pathway, a key driver in regulating normal epithelial cell growth and differentiation, also plays a role in promoting proliferation of malignant epithelial cells by increasing proliferation, adhesion and invasive capacity, and also by blocking apoptosis. For this reason, EGFR expression is associated with metastasis, late-stage disease, resistance to therapy and poor prognosis. Therapies targeting EGFR are now under development, such as antibodies to EGFR or EGFR-specific tyrosine kinase inhibitors. Gefitinib, also known as ZD 1839 or Iressa , is a low-molecular-weight compound that inhibits the activation of EGFR tyrosine kinase through competitive binding of the receptor. A 65-year-old woman presented with a 2-month history of asymptomatic, brown to black hairs on the nose tip that had been gradually thickening and lengthening (Fig. 1). Six months before, she had been diagnosed with metastatic lung adenocarcinoma and had undergone treatment with radiotherapy (whole brain and femur, 3000 cGy · 2 cycles) and chemotherapy (docetaxel 100 mg daily every 3 weeks for 2 months). Two months before, she began treatment with gefitinib 250 mg daily. One week after starting treatment, she noticed tiny brown to black spots on her nose tip. Ever since, hairs have been growing at these sites. When she presented to our department, the hairs were 1–3 mm in length, localized to the nose tip. There were no vellus hairs, which normally there should be. There was no abnormality of hair density or length at other body sites. She denied a personal history of other cutaneous problems, trauma or administration of any drugs such as might induce hair growth. Skin biopsy revealed multiple hair follicles in anagen phase that were located in the superficial dermis (Fig. 2). The hair shaft

A rare side-effect of systemic isotretinoin treatment: hoarseness

JEADV 2006, 20, 1328–1399