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V. Michael Holers MD

Head, Division of Rheumatology University of Colorado Denver


 

 

Dr. Holers research group performs both basic and translational research. A longstanding interest has been to decipher the roles of complement receptors and membrane regulatory proteins in the immune response, with a special emphasis on autoimmune diseases. Complement is a complex system of serum proteins which, upon activation, covalently bind targets (bacteria, viruses, immune complexes) and marks them as foreign. The interaction of complement with B cell receptors also results in substantial enhancement of humoral and cellular immunity. In addition to this role, excessive activation of complement is centrally involved in autoimmunity and the tissue damage that occurs in many inflammatory diseases involving organs such as the kidney. The Holers’ laboratory has developed human and mouse models in which to study these complement related biologic processes and to develop novel complement inhibitors. Candidate therapeutics derived from these studies have been advanced to clinical trials in humans.

With regard to translational research, Dr. Holers is a co-founder of SERA (Studies of the Etiology of Rheumatoid Arthritis), which is focused on understanding the early pathogenesis and natural history of RA. In that regard, we now know that autoimmune diseases such as RA begin years before clinical signs and symptoms are apparent, when at-risk individuals manifest highly predictive autoantibodies in their serum. By studying individuals in this period of time, SERA investigators have made novel findings suggesting that RA is initiated through a process linked to mucosal inflammation. This observation also suggests that additional therapeutic and/or prevention strategies could be considered for individuals in this at-risk but asymptomatic period. It is also relevant to determine how individuals transition from this autoantibody-positive, at-risk period to clinically active disease, and several studies are underway that are related to understanding these questions.
 
 

 

 

 1993              Arrived at UCD 
 1983-1985    Research Fellowship in Rheumatology - Washington University School of Medicine
 1983-1985    Research Associate - Howard Hughes Medical Institute, St. Louis, MO
 1981-1983    Clinical Fellowship in Rheumatology- University of Colorado School of Medicine, 
                       Denver, CO
 1979-1981    Residency - Internal Medicine Barnes Hospital, St. Louis MO
 1978-1979    Internship - Internal Medicine Barnes Hospital, St. Louis MO
 
Medical School: Washington University Medical School, St. Louis, Missouri

 




 


 2000-Present   Head, Division of Rheumatology - University of Colorado Denver
  
 1998-Present   Professor of Immunology - University of Colorado Denver
 
 1997-Present   Present Professor of Medicine - University of Colorado Denver
 
 1993-Present   Smyth Professor of Rheumatology - University of Colorado Denver
 
 1994-1998       Professor of Immunology - University of Colorado Denver
 
 1993-1997       Associate Professor of Medicine (with tenure) - University of Colorado Denver
 
 1992-1993       Associate Professor of Medicine (with tenure) - Washington University 
                         School of Medicine
 
 1987-1993       Member - Division of Biology and Biomedical Sciences, Washington University 
                         School of Medicine
 
 1987-1993       Assistant Professor of Pathology - Washington University School of Medicine
 
 1986-1993       Assistant Investigator - Howard Hughes Medical Institute
 
 1986-1992       Assistant Professor of Medicine - Washington University School of Medicine

 1985-1986       Instructor in Medicine - Washington University School of Medicine

 








 

 

PROFESSIONAL SOCIETY MEMBERSHIPS:
American Federation of Clinical Research
American College of Rheumatology
American Association of Immunologists
American College of Physicians
American Society for Clinical Investigation
Western Society for Clinical Investigation
International Complement Society
American Association of Physicians
Henry Kunkel Society
Clinical Immunology Society
 
EDITORIAL AND REVIEW:
1992-99             Associate Editor, Journal of Immunology
1995-2000         Associate Editor, Arthritis & Rheumatism
2013-                 Consulting Editor, Journal of Clinical Investigation
Ad hoc reviews  Immunity, Journal of Experimental Medicine,Journal of Clinical 
                          Investigation, Nature, Nature Immunology, Proceedings of the National 
                          Academy of Science, Molecular Immunology, Blood, Journal of Immunology,
                          Arthritis and Rheumatism
 
NATIONAL PEER GRANT REVIEW SERVICE:
1989-93             National Arthritis Foundation Biomedical Research Grant Review Committee
1993                  Ad hoc member "Research in causal mechanisms of SLE" RFA Study Section, 
                           NIAMS
1993                  Ad hoc member ALY Study Section, NIAID
1993-                 NIH P0-1 and R0-1 ad hoc reviews, special study sections
1993-                 Ad hoc reviewer for VA Career Development Awards
1991-                 Ad hoc reviewer for National Science Foundation
1996-2000        Member, Allergy and Immunology (ALY) Study Section, Center for Scientific 
                         Review, NIH
2000-02            Pfizer Postdoctoral Fellowship Academic Advisory Board
2000-                Ad hoc reviewer for Immune Tolerance Network
2000-06            Chair, Scientific Advisory Board, North American Rheumatoid Arthritis
                         Consortium (NARAC)
2001-04           Abbott Postdoctoral Fellowship Review Panel
2001-05           Advisory Board, Multiple Autoimmune Diseases Genetic  Consortium (MADGC)
2003                 Ad hoc member "Microcirculation and Target Organ Damage in Rheumatic and
                         Skin Diseases" RFA Study Section, NIAMS
2003-04           Chair, American College of Rheumatology Research and Education Foundation
                         Research Review Panel
2005                Chair, NIH CSR Special Study Section for Systemic Lupus Erythematosus 
                        Applications
2007-10           Chair, NIH CSR Special Study Sections
2012                Member, NIAMS P60 Centers Review Study Section
 
NATIONAL PROFESSIONAL ACTIVITIES:
1992-              American College of Rheumatology Abstract Selection Subcommittees
1997               Subcommittee Chairman, American College of Rheumatology National Meeting
                       Abstract Selection Committee
1995-98          Member, Committee on Research, American College of Rheumatology
1997-98          Annual Meeting Planning Committee, American College of Rheumatology
1998               ACR Basic Research Conference Co-Organizer
1995, 1998     Co-Chair, Complement Symposium, AAI Meeting
1998-2000      National Arthritis Foundation Publications Committee
1998-2000      International Complement Workshop Organizing Committee
1999               Co-Chair, ACR Basic Research Conference
1999-2002      Chair, Committee on Research, American College of Rheumatology
1999-2002      Member, Board of Directors, American College of Rheumatology Research
                        and Education Foundation
2000-02, 2004  Arthritis Foundation Fellows Research Conference Planning Committee
2000-01          Blue Ribbon Panel on Research, National Arthritis Foundation
2000-04          Founding Member and Secretary, International Complement Society
2002               Member, NIH Study Section Boundaries Team for Integrated Review 
                       Group (IRG) #10 (Immunology)
2001-03          Member, Abstract Oversight Committee, American College of Rheumatology
2002-04          Member, Board of Directors, American College of Rheumatology
2003-06          Program Committee Block Chair, American Association of Immunologists
2003-04          Chair, Task Force on Research Funding, American College of Rheumatology
2003-08          Steering Committee, NIH/NIAMS SLE Biomarkers Consortium
2004-07          Site Director, Lupus Clinical Trials Consortium 
2004-07          Chair, Scientific Advisory Council, American College ofRheumatology
                       Research and Education Foundation
2004-10          Member, Board of Directors, American College of Rheumatology 
                       Research and Education Foundation
2007               Member, ad hoc, FDA Guidance Panel “Abatacept”
2005-06          Chair, Rheumatoid Arthritis Initiative Task Force,American College 
                       of Rheumatology Research and Education Foundation
2007-09         Member, Nominating Committee, Henry Kunkel Society
2007-09         Member, ITN Strategic Planning Group for Autoimmunity
2011              Co-Chair, NIAMS Arthritis Biology Research Roundtable
2011-12        Co-Chair, American College of Rheumatology Blue Ribbon Task Force
                     on Academic Rheumatology
2011-           Member, Scientific Advisory Board, Lupus Research Institute
2011-2104   Member, American College of Rheumatology Board of Directors
2012-            Member, International Complement Society Board of Directors
2012-13       Member, NIAMS Centers Evaluation Working Group
2013            Member, NIAMS Target Evaluation Consortium Working Group
2013-           Member, National Arthritis Foundation RA Task Force
2013-           Member, Arthritis Foundation Great West Region Medical and Scientific
                    Committee
2014-          Chair, American College of Rheumatology Division Directors Task Force
2014-          Member, American College of Rheumatology Finance Committee
2014-          President-Elect, International Complement Society
2015-          Member, NIAMS Advisory Council
 
COMMUNITY ACTIVITIES:
1994-2008    Member, Board of Directors, Rocky Mountain Chapter, Arthritis Foundation
1996-2005     Executive Committee of the Board of Directors, Rocky Mountain Chapter, 
                      Arthritis Foundation
1997-2000     Chair, Medical and Education Committee, Rocky Mountain Chapter, Arthritis
                       Foundation
1998-2000     Secretary, Rocky Mountain Chapter, Arthritis Foundation
1999-2001     Member, Colorado Arthritis Advisory Committee
2000-02         House of Delegates, National Arthritis Foundation
2000-02         Chair-Elect, Rocky Mountain Chapter, Arthritis Foundation
2002-03         Chair, Rocky Mountain Chapter, Arthritis Foundation
2003-05         Chair, Board Development Committee, Rocky Mountain Chapter, Arthritis
                      Foundation

 

1974          Phi Beta Kappa 
1985          American Rheumatism Association Senior Fellowship Award
1988-91     Hulda Irene Duggan Investigator, Arthritis Foundation
1993          Member, American Society for Clinical Investigation (ASCI)
1996          Ecker Lectureship, Case Western Reserve University, Cleveland,OH
1997          Robert Wood Johnson Award, Arthritis Foundation
1997          Schwartz-Weinstein Research Award, Arthritis Foundation Rocky Mountain Chapter
1998          Harmon Foundation Award, Arthritis Foundation, Rocky Mountain Chapter
1999          Kroc Lectureship, University of Iowa, Iowa City, IA
1999          Volunteer Leadership Award, National Arthritis Foundation
2000          Member, American Association of Physicians (AAP)
2002          Member, Henry Kunkel Society
2003          Pfizer Visiting Professor, Medical University of South Carolina
2004          Inventor of the Year, University of Colorado Denver, School of Medicine
2007          Ogryzlo Day Merck Frosst Canada and Schering Canada Visiting Professor, 
                  University of Toronto
2008          Ephraim P. and Jean S. Engleman Visiting Professor, University of California San
                  Francisco
2008         Pfizer Visiting Professor, Emory University School of Medicine
2008         American College of Rheumatology Distinguished Basic Investigator Award
2009         University of Colorado Technology Transfer Lifetime Pinnacle Awardee
2009         Kroc Lectureship, University of Texas Southwestern, Dallas, TX
2009         Eric Bywaters Lectureship, Hammersmith Hospital, London, UK
2009         Physician Pro Tempore, Hospital for Special Surgery, New York, NY
2009         Christian Lectureship, Hospital for Special Surgery, New York, NY
2009         Freyberg Lectureship, Hospital for Special Surgery, New York, NY
2010         Senior Fellow of the American Asthma Foundation
2011         Castle Connolly Top Doctor
2011         Zvaifler Lectureship, University of California San Diego, San Diego,CA
2014         Cochran Lectureship, University of Alabama Birmingham
2015         Rheumatology Research Foundation Memorial Lectureship, San Francisco, CA​

 

 
The basic and translational research focus of my research is on two areas.
 
The first is the roles of complement receptors and membrane regulatory proteins in the immune response, with a special emphasis on B lymphocytes and autoimmune diseases.

With regard to the first area, complement is a complex system of serum proteins which, upon activation, covalently bind targets (bacteria, viruses, immune complexes, cell membranes) and marks them as foreign. These covalently attached complement fragments bind high affinity receptors on lymphocytes and FDCs. The interaction of complement with B cell receptors results in substantial enhancement of humoral immunity. In addition to this role, excessive activation of complement is centrally involved in the tissue damage that occurs in many inflammatory diseases involving organs such as the kidney. My laboratory has developed human and mouse models in which to study these complement related biologic processes.
 
The second is the role of autoantibodies and the evolution of autoimmunity in RA from the pre-symptomatic autoantibody-positive period through the onset of clinically active disease.

With regard to the second area, we now know that autoimmune diseases such as RA, SLE and Type 1 Diabetes Mellitus begin years before clinical signs and symptoms are apparent. That is because these individuals manifest highly predictive autoantibodies in their serum. This observation suggests that we must extend our study of the genetic epidemiology of autoimmune diseases such as RA into this important period, and that additional therapeutic and/or prevention strategies should be considered for individuals in this at-risk but asymptomatic period. It is also relevant to determine how individuals transition from this autoantibody-positive, at-risk period to clinically active disease. My research group has established several ongoing studies in RA that are related to these questions.

Specific areas of emphasis include:
 
1.  Roles of complement receptor type 2 (CR2, CD21) in B lymphocyte development and activation. Using both human and mouse CR2 as a model, we are analyzing the ways by which CR2 regulates B lymphocyte responses to antigens bound by complement. The specific mechanisms by which CR2 and other complement receptors act to modify B lymphocyte responses are incompletely understood, though we have shown that CR2 deficient mice have a markedly impaired humoral immune response. We are now studying the signaling responses of these receptor deficient B lymphocytes. We have also recently created human CR2 transgenic mice as a way to study structure-function relationships and the effects of over-expression of receptors on B cell development and tolerance. Finally, we are determining the three dimensional structure of the CR2 ligand binding sites for its three ligands (C3d, Epstein-Barr virus and CD23) using NMR, x-ray crystallographic and other structural techniques.

2.  Analysis of the role of complement during the development of SLE, RA and other autoimmune and inflammatory diseases. A recent interest is on the role of specific complement activation pathways (classical, alternative and lectin) in the initiation of injury. In murine studies we are using complement receptor knockouts and complement inhibitors we developed to determine how the alteration of these systems affects self tolerance and tissue injury. A major finding has been to determine that the alternative pathway and its amplification loop are absolutely essential to generate pathologic complement activation fragments in antibody-dependent and –independent disease models and to develop new generations of inhibitors to take advantage of that observation.  In patients, we have led a therapeutic trial of a complement inhibitor in patients with SLE and active glomerular disease and continue to be focused on learning how complement inhibition can positively affect patients with various human diseases.

3.   In addition to the above areas of emphasis, a study of pre-disease autoimmunity in patients at risk for the development of RA has also been initiated in collaboration with Dr. Jill Norris of the Department of Preventive Medicine and other members of the Division of Rheumatology. By using unique human populations at risk for developing RA, we are determining what RA-associated autoantibodies and other biomarkers are present that could predict the development of clinical disease. In addition, we have developed an animal model of the pathogenic role of a newly described autoantibody system directed to citrullinated antigens, commonly called anti-CCP antibodies. These studies have clearly shown that these autoantibodies are pathogenic and are opening up additional therapeutic targets and opportunities.
 
 
PATENTS (granted):
1. “3-Dimensional Structure of Complement Receptor Type 2 and Uses Thereof”, U.S. Patent 6,820,011, November 16, 2004
2. “Targeting complement factor H for treatment of diseases”, U.S. Patent 7,759,304, July 20, 2010
3.  “Anti-factor B antibodies” U.S. Patent 7,999,082, August 16, 2011
4. “Humaneered anti-factor B antibody” U.S. Patent 7,964,705, June 21, 2011
5.  “Complement receptor 2 targeted complement modulators”, U.S. Patent 8,007,804, August 30, 2011
6. “Biomarkers for rheumatoid arthritis”, European Patent 2158326, June 20, 2012
7. “Inhibition of factor B, the alternative complement pathway, and methods related thereto” U.S Patent 8652475, February 18, 2014
8. “Non-invasive detection of complement-mediated inflammation using CR2-targeted nanoparticles” U.S. Patent 8,840,868, September 23, 2014
9. “Inhibition of the alternative complement pathway for treatment of traumatic brain injury, spinal cord injury and related conditions” U.S. Patent 8,911,733, December 14, 2014
 

Publications (NCBI publication list)