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

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