Gender	Female
E-mail	miriam.merad@mssm.edu
Education and Training	M.D., University of Algiers
	M.S. (DEA), Hospital Saint Louis (University Paris VII)
	Ph.D., Stanford University and Hospital Saint Louis
	Residency(Interne des Hospitaux), Hospital Saint Louis (University Paris VII)
	Fellowship, Stanford University

Merad Lab Website


Assistant: Tiffany Jones
               (212) 659-8284

Education and Training	M.D., University of Algiers
	M.S. (DEA), Hospital Saint Louis (University Paris VII)
	Ph.D., Stanford University and Hospital Saint Louis
	Residency(Interne des Hospitaux), Hospital Saint Louis (University Paris VII)
	Fellowship, Stanford University

Functional diversity of non lymphoid tissue dendritic cells
Although there is no doubt that DCs represent the major antigen presenting cell population involved in T cell priming, recent advances in DC biology show that they have a wider role in microbial immunity than previously envisioned. DCs appear to interact with a variety of cell types and have immune functions beyond the simple presentation of antigen for effective T cell priming. This discovery has merged with the growing realization over the past decade that DCs, at least in lymphoid organs, consist of various subsets. The identification of distinct DC populations and evidence that DCs play quite a diverse role in both innate and adaptive antiviral immune responses leads to the conclusion that individual DC subsets may be quite specialized in their response to infection. However in contrast to lymphoid organ DCs the phenotypical and functional diversity of DCs that populate non-lymphoid tissues remain poorly studied. The cytokines and transcription factors that regulate their development and differentiation from hematopoietic progenitors have not been clearly identified. In this project we aim 1/ to identify the diversity of DCs in non lymphoid tissues including the skin, lung, gut, liver, kidney, pancreas, and heart 2/ to Identify the factors that control the diversity of DC populations in non-lymphoid tissues in humans and mice, and 3/ to determine the developmental pathways that give rise to functionally specialized DC subsets in the periphery.

Vaccination strategies for the treatment of hematological malignancies
Allogeneic hematopoietic cell transplantation (allo-HCT) is potentially curative treatment for many patients with high-risk hematologic malignancies including leukemia and agressive lymphoma and myeloma. The success of allo-HCT is largely based on immunologic graft-versus-tumor (GVT) effects mediated by allogeneic T lymphocytes present in the graft. Using mouse allo-HCT models, we and others have identified host dendritic cells (DCs) as the key initiators and regulators of GVT effects. However, DC based vaccination strategies have been little studied in the context of allo-HCT in patients. The goal of this project is to use clinical relevant mouse models to test the benefit of novel vaccination strategies to initiate donor T cell specific response to the malignant hematopoietic cell clone. Based on recent results obtained in mice, we have initiated a series of clinical trials to test the benefit of DC vaccine to increase antitumor response in patients that receive allo-HCT.

In addition to inducing GVT, allogeneic T cells also lead to graft versus host reactions directed against normal host tissues resulting in graft versus host disease (GVHD), a potentially life-threatening complication that limits the success of allo-HCT. GVHD may manifest as inflammation of the skin, liver and gut. According to the degree of genetic disparity between allogeneic donor and recipient, GVHD may occur in up to 75%, and may lead to death in up to 20% of transplant recipients. Therefore, while preserving beneficial GVT effects, a major objective in allo-HCT is the prevention of GVHD. We and other have shown that host dendritic cells play a key role in this process. In particular we have shown that epidermal DCs, also called Langerhans cells resist the transplantation regimen and are sufficient to induce cutaneous GVHD in mice. Recent data from the laboratory show that human Langerhans cells are also more resistant to the transplantation regimen compared to other DC populations. Based on these results we hypothesized that the predilection of GVHD to the skin may be due to the persistence of host DCs in these tissues. One aim of this project is to develop strategies aiming at depleting recipient DCs to improve GVHD in patients.  Another aim of this project is to examine th e role of liver and gut DCs in the induction of GVHD in these tissues.

In vivo manipulation of Dendritic cells (DCs) to induce antitumor immunity
The ability of tumors to escape the immune system has been a major obstacle to the development of effective tumor immunotherapy.  Both central and peripheral immune tolerance have been implicated in the failure of tumor bearing hosts to mount an immune response to their tumors. Central tolerance may play a fundamental role in the lack of response against self-tumor associated antigens (Ags), while peripheral tolerance may explain the lack of response against tumor specific Ags. DCs are believed to play a critical role in anti-tumor immune responses.  These cells are the most potent antigen presenting cells (APCs) known, uniquely capable of inducing immunity to newly introduced Ags. Based on the recognition of the central role of DCs in initiating immune responses, a variety of strategies have been devised to use DCs to stimulate immunity against tumor Ags. Most of these strategies rely on the activation and maturation of DCs  ex vivo and their subsequent reinfusion to tumor bearing recipients after a pulse with tumor Ags expressed as peptides, protein or nucleic acids. However, several studies show that injected DCs are very inefficient at migrating to the draining lymph nodes and interact with T  lymphocytes. Recent data from the laboratory also suggest that DCs are functionally diverse and that distinct DC populations have different immune functions therefore in vitro derived DCs may not recapitulate well the immune function of tissue DC present in vivo . In addition,  ex vivo manipulation of DCs  is time consuming and costly, requires the use of numerous cytokines and exposes the patient to increased risk of infection. To avoid manipulation of DCs in vivo, we are currently developing several approaches to expand, load and activate DCs in vivo to induce therapeutic antitumor immunity. 

Merad M, Manz M. Dendritic cells in hematopoiesis. Blood;: in press.

Merad M, Ginhoux F, Collin M. The origin, homeostasis and function of langerin+ cells in mice and humans. Nature Reviews Immunology 2008; 8(12): 935-947.

Nagao K, Ginhoux F, Leitner WW, Bennett CL, Clausen BE, Merad M, Udey MC. Characterization of Phenotypically and Functionally Distinct Dendritic Cell Subpopulations in Skin. PNAS;: in press.

Haniffa M, Ginhoux F, Wang X, Bigley V, Abel M, Dimmick I, Bullock S, Grisotto M, Booth T, Hilkens C, Merad M, Collin M. Differential rates of replacement of human dermal dendritic cells and macrophages during hematopoietic stem cell transplantation. JEM 2009;: in press.

Jakubzick C, Bonito AJ, Bogunovic M, Merad M, Randolph GJ. Lymph-migrating, tissue-derived dendritic cells are minor constituents within steady state lymph nodes. J Exp Med 2008; 205(12): 2839-2850.

Waskow C, Liu K, Darrasse-Jeze G, Guermonprez P, Ginhoux F, Merad M, Shengelia T, Yao K, Nussenzweig M. The receptor tyrosine kinase Flt3 is required for dendritic cell development in peripheral lymphoid tissues. Nature Immunology 2008; 9: 676-683.

Merad M, Ginhoux F. The Arborising Genealogy of DC: New Stem Or Just Another Branch?. Nature Immunology 2007; 8(11): 1199-1201.

Ginhoux F, Collin M, Bougunovic M, Abel M, Leboeuf J, Helft J, Ochando J, Kissenpfennig A, Malissen B, Grisottos M, Snoeck H, Randolph G, Merad M. Blood-Derived Dermal Langerin+ Dendritic Cells Survey the Skin in the Steady state. J Exp Med 2007; 204(13): 3133-3146.

Bogunovic M, Ginhoux F, Wagers A, Loubeau M, Isola LM, Lubrano L, Najfeld V, Phelps RG, Grosskreutz C, Scigliano E, Frenette PS, Merad M. Identification of a radio-resistant and cycling dermal dendritic cell population in mice and men. J Exp Med 2006 Nov; 203(12): 2627-2638.

Ginhoux F, Tacke F, Angeli V, Bogunovic M, Loubeau M, Dai XM, Stanley ER, Randolph GJ, Merad M. Langerhans cells arise from monocytes in vivo. Nat Immunol 2006 Mar; 7(3): 265-273.