Tuesday, January 10, 2017

Virtual Memory T cells

New article brings into question how T cell memory should be defined.

We conducted this research to answer a fundamental question in immunology- Where do antigen inexperienced CD4+ T cells reside? 

Currently, it is widely accepted that central and effector memory CD4+ T cells originate from naïve T cells after they have encountered their cognate antigen in the setting of appropriate co-stimulation. However, if this were true the diversity of T cell receptor (TCR) sequences within the naïve T cell compartment should be far greater than that of the memory T cell compartment, which is not supported by TCR sequencing data. In fact the vast majority of T cells with a "memory" phenotype do not appear to have undergone a strong clonal expansion event.

 In our study we demonstrate that aged mice with far fewer naïve T cells, respond to the model antigen, hen eggwhite lysozyme (HEL), by utilizing the same TCR sequence as their younger counterparts. CD4+ T cell repertoire analysis of highly purified T cell populations from HEL-naive animals revealed that the HEL-specific clones, within these mice, displayed effector and central “memory” cell surface phenotypes even though they had never encountered the HEL antigen. Although cross reactivity to some other foreign antigen exposure could have explained these results, the effector and central “memory” HEL-specific T cells that were detected resided at an extremely low frequencies, identical to their frequency within the naive T cell compartment. Thus, any prior cross recognition event was not strong enough to have induced an expansion of the HEL-specific T cells, at least not one that could be detected above the background level that was seen in the naive T cell compartment. In our experiments the HEL-inexperienced CD4+ T cells were found to reside within the naïve, regulatory, central memory, and effector memory T cell populations at similar frequencies.  The vast majority of the other CD4+ T cells within the regulatory and memory populations were also unexpanded.

 These findings support a new paradigm for CD4+ T cell maturation in which a specific clone can undergo a differentiation process to exhibit a “memory” or regulatory phenotype without having undergone a clonal expansion event. They also demonstrate that a foreign-specific T cell is just as likely to reside within the regulatory T cell compartment as it would the naïve compartment, arguing against the specificity of the regulatory T cell compartment being skewed towards self-reactive T cell clones. Finally, we demonstrate that the same set of foreign T cell clones are repetitively generated throughout adulthood.

Trends In NIH Funding

The DEATH of the PHYSICIAN SCIENTIST



In this article published in JAMA Dermatology we demonstrate that MD-only physicians with NIH-funded research programs will become nonexistent in the near future if the current downward trend in federal funding continues. When tracked against PhD and MD/PhD researchers, physicians with ONLY and MD degree are losing funding at a dramatic rate. For more on this topic please see our article in JAMA Dermatology (Click Here-> http://bit.ly/Fundtrend). 



Figure Legend: Graph-> The dollar amount of NIH grants awarded to investigators with MD degrees has decreased significantly (β = −1.35, R2 = 0.81). Meanwhile, the trends for MD/PhD and PhD investigators are not significant (β = 0.25, R2 = 0.15 vs β = −0.24, R2 = 0.03, respectively).





For more interesting trends please see our recent article in JAMA Dermatology-> http://bit.ly/Fundtrend

Guillaume Luxardi, PhD




Experience



Post-Doc Scholar

UC Davis School of Medicine Dept. of Dermatology
 – Present (3 years 1 month)Institute for Regenerative Cures
The research I am performing is allowing me to acquires expertise in Immunology and Cancer Biology. We are currently designing genetically engineered T Cells and analyzing the phenotypes induced on Melanoma cells.



Post-Doc Scholar

UC Davis School of Medicine Dept. of Dermatology
 –  (2 years 6 months)Institute for Regenerative Cures
The research I undertake allow me to acquires an interdisciplinary approach combining embryology, genetics, cell and molecular biology with electrophysiology in the context of animal development and regeneration. I am focusing on the integration of bio-physical and bio-chemical cue during tissue repair and regeneration as well as pattern formation during animal development.



ATER (non tenure track Faculty)

Aix-Marseille University
 –  (1 year)Developmental Biology Institute of Marseille-Luminy
Lecture and laboratory courses in Cellular biology to Bachelor and Master Students in Biology.

The research I undertook focuses on elucidating the biological functions and integration of BMP, FGF, Nodal and Notch signals during differentiation and morphogenesis in the Xenopus embryo.



Monitor / PhD student

Aix-Marseille University
 –  (3 years 1 month)Developmental Biology Institute of Marseille-Luminy
The research I undertook focuses on elucidating the biological functions and integration of BMP, FGF, Nodal and Notch signals during differentiation and morphogenesis in the Xenopus embryo.

Lecture and laboratory courses in Drosophila genetics to Bachelor Students in Biology



Graduate Research Assistant

Aix-Marseille University
 –  (4 months)Developmental Biology Institute of Marseille-Luminy
The research I undertook focuses on the establishment of mono layer murine Embryonic Stem Cell (ESC) culture and neural differentiation and on the description of the expression pattern of glypicans genes in mice embryonic and new born brain

Michiko Shimoda, PhD



Position: Assistant Professor, Co-Director Immune Monitoring Shared Resource

PROFILE


Immunologist with over 20 years of experience in broad human and mouse immunology with emphasis in B cell biology and antigen presenting cell functions. Conducted basic and translational research projects in the area of vaccine, autoimmune diseases and cancers with various animal disease models in academic and private institutes.


RESEARCH INTEREST


* Glycans as a tool to modulate immune response

* To identify and characterize natural glycans (human milk glycans and plant glycans) that can modulate antigen-presenting cell function and differentiation.

* To identify key signaling events in immune cells induced by glycans, which are required for glycan-mediated immune modulatory functions.

* To test immune modulatory functions of glycans in animal models of cancers, autoimmune diseases, or in vaccination.

* Immune monitoring of patients with cancers and autoimmune diseases

RESEARCH EXPERIENCE


University of California at Davis, School of Medicine, Department of Dermatology,
Assistant Adjunct Professor


* The anti-inflammatory role of human milk glycans.

* Characterization of anti-inflammatory functions of human milk glycans.

* Identification of key signaling events in human dendritic cells induced by glycans, which are required for glycan-mediated anti-inflammatory functions.

(manuscript in preparation)

* Glycans as a tool for immune therapy

* Identification and characterization of natural glycans (human milk glycans and plant glycans) to modulate myeloid lineage cell function and differentiation.

Medical College of Georgia, School of Medicine,
Assistant Professor


* B cell antigen presentation in immune responses.

* Employed unique B cell restricted MHC-II conditional knockout mice to help understanding the role of B cell antigen presentation in immune response.


Utsunomiya University, Utsunomiya, Japan
Instructor


* Repertoire analysis of mucosal IgA response

* Generated over 20 IgA clones from murine Peyers’ patches using hybridoma technology.

* Characterized mucosal IgA repertoire specificity.

* Understanding the mechanism of memory B cell generation during immune response

* Studied the mechanism of high-affinity B cell selection in germinal centers.


University of Tokyo, Tokyo University of Agricultural and Technology, Tokyo, Japan
PhD


* Understanding the mechanism of high-affinity memory B cell generation for mucosal vaccine development.

* Demonstrated for the first time that high-affinity IgA memory B cells are generated through germinal center response in mucosal associated lymphoid tissues.


INDUSTRY EXPERIENCE


Research Center for Allergy and Immunology, RIKEN, Yokohama, Japan

Research Scientist

Morinaga Milk Industry CO., Tokyo, Japan

Research Scientist

TECHNICAL SKILLS


* Flowcytometry: FACSCanto, FACSFortessa and FACSAriam with multiplex flow cytometry for immune- subset markers with intracellular cytokine staining, phospho- specific flow cytometry.

* Immune-monitoring assays: ELISA assays, ELISPOT and Luminex assays.

* Immune histochemistry.

* Molecular Biology: General molecular biology techniques including PCR, quantitative RT-PCR, cloning and mutagenesis.

* Protein purification: HPLC, gel electrophoresis analysis, Western blotting.

* Antibody production: animal immunization, cell culture, hybridoma generation.

* Animal handling: mouse, rat, guinea pig, and rabbit.

* Animal models: experimental autoimmune encephalomyelitis, colitis, T1 diabetes, skin transplantation, adoptive lymphocyte transfer, bone marrow transfer, xenograft cancers (B16 melanoma, PEL and NHL).

EDUCATION


* Ph.D. Tokyo University of Agriculture and Technology
Tokyo, Japan (2002) Mucosal Immunology

* PhD course University of Tokyo
Tokyo, Japan (1990-1991) Molecular Biology

* MS University of Tokyo, Tokyo, JAPAN
Tokyo, Japan (1984-1986) Agricultural Biochemistry


AWARDS, HONORS AND FELLOWSHIPS


* Research Award (Immunology) by Becton Dickinson to study autoimmune skin diseases.

* Travel Grants from the American Association of Immunologist for attending the annual meetings and International Congress of Immunology

* Travel Grants from the NIAID to attend an annual American Association of Immunologist meeting.

* Presidential Guest Scientist of Tokyo University of Scientist in support with international collaboration on immune regulation.

* Fellowship for young overseas researchers from Japanese government in support with visiting research activity in Dr Garnett Kelsoe’s laboratory, University of Maryland.

GRANTS


* Seed grant Shimoda, M. (PI) 6/01/2016 – 05/31/2017 (UC Davis Dermatology)
“Characterizing sialyl milk oligosaccharides with anti-inflammatory functions” The major goal of this project is to characterize milk oligosaccharides with anti-inflammatory functions using in vitro culture of human dendritic cells.

* PSRP00054 Shimoda, M. (PI) 10/01/2011 – 09/30/2012 (MCG Pilot Study Research Program)
“Regulatory function of IL-10-producing CD8 T cells in immunity and autoimmunity” The major goal of this project was to define the regulatory role of IL-10 producing CD8 T cells in mouse T1 diabetes model.

* NIAID R21 AI064752-01A2 Shimoda, M. (PI) 09/30/2007 – 08/31/2011 (NIH/NIAID)
“Long-lived plasma cell differentiation” The major goal of this project was to define the role of MHC-II-restricted antigen presentation in long-lived plasma cell differentiation of memory B cells.

* NIAMS R03 5R03AR52470-2 Shimoda, M. (PI) 3/01/06-2/28/11 (NIH/NIAMS)
“B cell antigen presentation in models of B cell autoimmunity” The major goal of this project was to understand the role of MHC-II and CD40/CD40L signals in a mouse model of B cell autoimmunity.

* MCGRI grant Shimoda, M. (PI) 10/01/09-09/30/10 (Medical College of Georgia)
“Autonomous CD40 signaling in lymphomagenesis” The aim was to study the role of constitutive CD40 signaling in B malignancy.

* Matuszak Foundation for lupus research Shimoda, M. (PI) 09/01/2008 – 08/30/2009 (Matuszak Foundation, Medical College of Georgia)
“Role of stromal cell surface heat shock proteins in Lupus” The aim was to test the hypothesis that HSP90/DNA complexes displayed on the surface of dying cells trigger B cells to make self-reactive antibodies.

* MCGRI grant Shimoda, M. (PI) 08/01/04-07/31/06 (Medical College of Georgia)
“MHC-II dependent antigen presentation in long-lived plasma cell differentiation” Studies of the role of B cell MHC-II in the differentiation of long-lived plasma cells in bone marrow.

* Grant-In-Aid Shimoda, M. (PI) 04/01/02-03/31/03 (Japanese government)
“Genetic analysis of B cell memory response in LT-beta knock-out mice” The aim was to study follicular dendritc cell (FDC) function B cell memory response generation by analyzing LT-beta knockout mice, which form germinal centers without FDC networks.

NCBI bibliography

Laura Olney, MA


Laura Olney, MA

Alina Marusina, PhD

Experience 




Assistant Researcher

UC Davis
 – Present (5 years)
Reserach

Michelle Cheng, M.D.

Michelle Yaolin Cheng, M.D.

Position: Clinical Research Fellow


Dr. Cheng completed her undergraduate studies at the University of California, Berkeley and earned her medical degree from the University of Pittsburgh School of Medicine.  After completing an internship in Pittsburgh and a clinical fellowship at Stanford she joined the clinical research team at UC Davis, where she has been influential in the design of a variety of investigator-initiated clinical studies.  She is also the Sub-I on a variety of company sponsored clinical trials.


Education

      University of California, Davis, Clinical Research Fellowship

      Sacramento, CA

July 2015 - ongoing

 

      University of Pittsburgh Medical Center, Transitional Year

      Pittsburgh, PA

June 2014 - June 2015

      University of Pittsburgh School of Medicine

      Pittsburgh, PA

M.D. August 2010 - May 2014

University of California, Berkeley, CA
Molecular and Cell Biology
Emphasis in Immunology & Pathogenesis
B.A. August 2005 - May 2009

Monday, January 9, 2017

Emanual Maverakis, MD



Emanual Maverakis, MD-    Principal Investigator

Dr. Maverakis runs a UC Davis clinic that specializes in the treatment of patients with severe immune-mediated diseases involving the skin and skin cancers such as melanoma and cutaneous T cell lymphoma. He is also an immunology researcher who holds early career awards from the Howard Hughes Medical Institute and the Burroughs Wellcome Fund.
“In order to gain insight into the pathogenesis of autoimmunity the first step is to identify and characterize the T cells involved.”
Dr. Maverakis became interested in immunology as an undergraduate at the University of California-Los Angeles where he earned departmental honors for his work on a mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis. He then continued his research endeavors at Harvard Medical School (HMS) in Boston where he graduated summa cum laude in 2003. He is in a elite group of only 15 students in over 220 years to have graduated with highest honors from HMS. After completing an internship in internal medicine at Harvard’s Beth Israel Deaconess Medical Center, Dr. Maverakis came to UC Davis to complete a residency in dermatology and in 2007 he joined the faculty. He holds appointments in the Department of Dermatology and in the Department of Medical Microbiology and Immunology. 
His lab investigates the pathophysiology of autoimmunity, how T cells (a type of white blood cell) develop and mature, and cancer immunotherapy.  His group is also interest in how foods interact with our immune system; how the immune system recognizes cancer, especially melanoma; developing novel hydrogels, especially with regards to delivering stem cells and immunotherapeutics; clinical trial design, and outcome measures.  Some diseases of special interest include psoriasis, scleroderma, pyoderma gangrenous, pemphigus vulgaris, bullous pemphigoid, melanoma, and cutaneous T cell lymphoma.  

Education
B.S. Microbiology and Molecular Genetics-                 University of California, Los Angeles
M.D. Medicine with special studies in Immunology-                        Harvard Medical School

Honors and Awards
MD Summa Cum Laude, Harvard Medical School | NIH Director's New Innovator Award, National Institutes of Health | Career Award for Medical Scientists, Burroughs Welcome Fund | Physician-Scientist Career Award, Howard Hughes Medical Institute | PECASE, President Barack Obama