The neural crest gives rise to numerous cell types, including Schwann cells, neurons, and melanocytes. The extent to which adult neural crest-derived cells retain plasticity has not been tested previously. We report that cutting adult mouse sciatic nerve induces pigmentation around nerve fascicles, among muscle bundles, and in the hypodermis. Pigmented cells are derived from adult nerve, because pigmentation occurs even when nerve fragments are grafted into tyrosinase null albino mice. Pigmentation defects are pervasive in patients with neurofibromatosis type 1 (NF1). Mice hemizygous for Nf1 mutations show enhanced pigmentation after nerve lesion and occasionally form pigmented and unpigmented tumors. The Nf1 nerve and the Nf1 host environment both contribute to enhanced pigmentation. Grafted purified Nf1 mutant glial cells [S100(+)-p75NGFR(+)-GFAP(+)-EGFR(+) or S100(+)-p75NGFR(+)-GFAP(+)-EGFR(-)] mimic nerve-derived pigmentation. The NF1 protein, neurofibromin, is a Ras-GAP that acts downstream of a few defined receptor tyrosine kinases, including [beta-common (beta(c))] the shared common receptor for granulocyte and monocyte colony-stimulating factor, interleukin-3 (IL3), and IL5. Cytokines in the environment have the potential to suppress pigmentation as shown by nerve injury experiments in null mice; when is beta(c) absent or Nf1 is mutant, melanogenesis is increased. Thus, the adult nerve glial cell phenotype is maintained after nerve injury by response to cytokines, through neurofibromin.

Loss of axonal contact characterizes Schwann cells in benign and

We propose that a high risk vascularized cornea behaves like a vascularized solid organ transplant. The early production of CXCL1/KC is crucial to the induction of T-cell chemoattractants necessary for the recruitment of allospecific CD4 T cells into the graft. In vivo neutralization of CXCL1/KC represents a potential novel therapy that could be used to increase the survival rate of high-risk vascularized corneal allografts.

559 Background: Renal cell carcinoma (RCC) tumor vasculature is abnormal and does not provide nutritive blood flow, which results in regions of hypoxia. This hypoxia contributes to the immune tolerance of tumor cells by impeding the homing of cytotoxic T cells into tumor parenchyma. In addition, tumor angiogenesis enhances activity of myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM) that suppress innate anti-cancer immunity. It has been demonstrated in preclinical models that antiangiogenic therapy decreased the number of MDSCs and changed polarization of TAMs from an immunosuppressive (M2-like) to an immunostimulatory (M1-like) phenotype. We hypothesized that therapy with bevacizumab will normalize the tumor vasculature, promote M1-like phenotype of TAMs, and thus potentiate the immunotherapeutic activity of pembrolizumab. As a prerequisite to testing this hypothesis, the objective of this study was to establish the safe dose of bevacizumab when used in combination with pembrolizumab. Methods: Our subject population included males and females (age > 18 y) with metastatic clear cell RCC after failure of at least one systemic therapy. In this Phase Ib dose escalation study, pembrolizumab (200 mg fixed dose every 3 weeks) was given in combination with bevacizumab (either at 10 mg/kg or 15 mg/kg every 3 weeks). The primary endpoint was to establish the maximum safe dose. Results: 12 subjects have been enrolled: 10 males (ages 33-68 y, mean: 52.7, median: 54.5) and 2 females (ages 61 and 62 y). To date 3 patients have received 1 cycle; 2 patients have received 2, 3, and 4 cycles each; and there are single patients who have received 5, 6, and 7 cycles each. No dose-limiting toxicity or serious adverse events related to the study drug have been reported. There were no grade 3 or 4 drug-related toxicities noted, and the most common grade 1 and 2 toxicities were diarrhea, fatigue, fever, hypertension, nausea, rash, and rigors. Conclusions: The 200 mg fixed dose of pembrolizumab and 15 mg/kg dose of bevacizumab, both given every 3 weeks, was determined to be safe and recommended for a multicenter Phase 2 study that is ongoing. Clinical trial information: NCT02348008.