35 research outputs found
From a Biomarker to Targeting in a Proof-Of-Concept Trial
Background There is high medical need for safe long-term immunosuppression
monotherapy in kidney transplantation. Selective targeting of post-transplant
alloantigen-(re)activated effector-T cells by anti-TNF antibodies after global
T cell depletion may allow safe drug minimization, however, it is unsolved
what might be the best maintenance monotherapy. Methods In this open,
prospective observational single-centre trial, 20 primary deceased donor
kidney transplant recipients received 2x20 mg Alemtuzumab (d0/d1) followed by
5 mg/kg Infliximab (d2). For 14 days all patients received only tacrolimus,
then they were allocated to either receive tacrolimus (TAC, n = 13) or
sirolimus (SIR, n = 7) monotherapy, respectively. Protocol biopsies and
extensive immune monitoring were performed and patients were followed-up for
60 months. Results TAC-monotherapy resulted in excellent graft survival (5yr
92%, 95%CI: 56.6–98.9) and function, normal histology, and no proteinuria.
Immune monitoring revealed low intragraft inflammation (urinary IP-10) and
hints for the development of operational tolerance signature in the TAC- but
not SIR-group. Remarkably, the TAC-monotherapy was successful in all five
presensitized (ELISPOT+) patients. However, recruitment into SIR-arm was
stopped (after n = 7) because of high incidence of proteinuria and
acute/chronic rejection in biopsies. No opportunistic infections occurred
during follow-up. Conclusions In conclusion, our novel fast-track TAC-
monotherapy protocol is likely to be safe and preliminary results indicated an
excellent 5-year outcome, however, a full–scale study will be needed to
confirm our findings. Trial Registration EudraCT Number: 2006-003110-1
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Control of pelage hair follicle development and cycling by complex interactions between follistatin and activin
Members of the transforming growth factor β/bone morphogenetic protein (TGF‐β/BMP) family are involved in the control of hair follicle (HF) morphogenesis and cycling. The activities of several members of this family (activins and BMP‐2, ‐4, ‐7, and ‐11) are controlled by antagonists such as follistatin. Because follistatin‐deficient mice show abnormalities in vibrissae development, we explored the role of follistatin and activin in pelage HF development and cycling. We show here that during HF development follistatin mRNA was prominently expressed by hair matrix and outer root sheath keratinocytes as well as by interfollicular epidermal cells, whereas activin βA mRNA was mainly expressed in dermal papilla cells. Compared with age‐matched wild‐type controls, both follistatin knockout mice and activin βA transgenic mice showed a significant retardation of HF morphogenesis. Treatment of wild‐type embryonic skin explants with follistatin protein stimulated HF development. This effect was inhibited by addition of recombinant activin A protein. Activin βA transgenic mice demonstrated retardation of catagen entry, down‐regulation of BMP‐2, and up‐regulation of expression of its antagonist matrix GLA protein. These observations suggest that follistatin and activin interaction plays an important role in both HF development and cycling, possibly in part by regulating expression of BMP‐2 and its antagonist
Substantial Sex-Dependent Differences in the Response of Human Scalp Hair Follicles to Estrogen Stimulation In Vitro Advocate Gender-Tailored Management of Female Versus Male Pattern Balding
In this study, it was investigated how estrogens (17-β-estradiol, E2) affect the estrogen receptor (ER) expression and gene regulation of male versus female human scalp hair follicles in vitro. Anagen VI follicles from frontotemporal scalp skin were microdissected and organ-cultured for up to 9 d in the presence of E2 (1–100 nm). Immunohistochemistry was performed for ERβ-expression, known to be predominant in human scalp hair follicles, and for TGF-β2-expression (as negative key hair growth modulator), and E2-responsive genes in organ-cultured human scalp hair follicles (48 h, 10 nM) were explored by cDNA microarray, using a commercial skin focus chip (Memorec, Cologne, Germany). The distribution pattern of ERβ and TGF-β2-immunoreactivity differed between male and female hair follicles after 48 h culture. Of 1300 genes tested, several genes were regulated sex-dependent differently. The study reveals substantial sex-dependent differences in the response of frontotemporal human scalp hair follicles to E2. Recognition and systematic dissection of the E2-dependent gene regulation will be crucial for the development of more effective, gender-tailored management strategies for female versus male pattern balding