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The Laboratory of Joshua Thurman, M.D.

 

The kidney is one of the most common targets of autoimmune and auto-inflammatory injury. The overarching goals of the Thurman laboratory are to:

i) Study the mechanisms that render the kidney susceptible to immunologic injury

ii) Develop non-invasive methods of detecting and monitoring immune activation in the kidney

iii) Develop novel therapeutic strategies to protect the kidney

 

One topic of active investigation is identification of the mechanisms by which the complement system is activated after aseptic injury of the kidney (such as that caused by ischemia or toxins). Although it has been appreciated for decades that the complement system is activated by immune-complex deposition within the kidney, we have also demonstrated that ischemic and toxic injury of the kidney engages the complement system. Employing in vivo and in vitro models of ischemic acute kidney injury, we have demonstrated that ischemia alters complement regulation by tubular epithelial cells. These results indicate that a loss of complement regulation by the injured kidney is sufficient to cause complement activation, even in the absence of a complement activator such as immunoglobulin.

 

In addition to studying the mechanisms of innate immune activation, the laboratory has worked to develop new immunomodulatory therapeutic agents and novel methods for monitoring renal inflammation. We have developed therapeutic complement inhibitors and have tested these agents in models of renal disease. In collaboration with radiologists and biomechanical engineers at the University of Colorado, the laboratory has also developed an MRI contrast agent that is targeted to molecular markers of inflammation (C3 activation fragments). Using MRI pulse-sequences designed to detect this targeted agent, a method was developed to non-invasively monitor renal inflammation in a mouse model of lupus nephritis. Such a method can be used to identify patients likely to benefit from complement inhibitory therapy and monitor the response of such patients to therapy. ​

 

Dynamic control of the complement system by modulated expression of regulatory proteins.Thurman JM, Renner B. Lab Invest. 2011 Jan;91(1):4-11. Epub 2010 Oct 4.

 

B cell subsets contribute to renal injury and renal protection after ischemia/reperfusion.

Renner B, Strassheim D, Amura CR, Kulik L, Ljubanovic D, Glogowska MJ, Takahashi K, Carroll MC, Holers VM, Thurman JM.J Immunol. 2010 Oct 1;185(7):4393-400. Epub 2010 Sep 1.

 

The complement inhibitors Crry and factor H are critical for preventing autologous complement activation on renal tubular epithelial cells. Renner B, Coleman K, Goldberg R, Amura C, Holland-Neidermyer A, Pierce K, Orth HN, Molina H, Ferreira VP, Cortes C, Pangburn MK, Holers VM, Thurman JM. J Immunol. 2010 Sep 1;185(5):3086-94. Epub 2010 Jul 30.

 

Renal inflammation: targeted iron oxide nanoparticles for molecular MR imaging in mice.

Serkova NJ, Renner B, Larsen BA, Stoldt CR, Hasebroock KM, Bradshaw-Pierce EL, Holers VM, Thurman JM. Radiology. 2010 May;255(2):517-26. Epub 2010 Mar 23.

 

Alternative pathway of complement in children with diarrhea-associated hemolytic uremic syndrome. Thurman JM, Marians R, Emlen W, Wood S, Smith C, Akana H, Holers VM, Lesser M, Kline M, Hoffman C, Christen E, Trachtman H. Clin J Am Soc Nephrol. 2009 Dec;4(12):1920-4. Epub 2009 Oct 9.

 

Oxidative stress renders retinal pigment epithelial cells susceptible to complement-mediated injury. Thurman JM, Renner B, Kunchithapautham K, Ferreira VP, Pangburn MK, Ablonczy Z, Tomlinson S, Holers VM, Rohrer B. J Biol Chem. 2009 Jun 19;284(25):16939-47. Epub 2009 Apr 21.

 

The alternative pathway of complement is activated in the glomeruli and tubulointerstitium of mice with adriamycin nephropathy. Lenderink AM, Liegel K, Ljubanović D, Coleman KE, Gilkeson GS, Holers VM, Thurman JM. Am J Physiol Renal Physiol. 2007 Aug;293(2):F555-64. Epub 2007 May 23.

 

C3a is required for the production of CXC chemokines by tubular epithelial cells after renal ishemia/reperfusion. Thurman JM, Lenderink AM, Royer PA, Coleman KE, Zhou J, Lambris JD, Nemenoff RA, Quigg RJ, Holers VM. J Immunol. 2007 Feb 1;178(3):1819-28.

 

Triggers of inflammation after renal ischemia/reperfusion. Thurman JM. Clin Immunol. 2007 Apr;123(1):7-13. Epub 2006 Oct 24.

 

Treatment with an inhibitory monoclonal antibody to mouse factor B protects mice from induction of apoptosis and renal ischemia/reperfusion injury. Thurman JM, Royer PA, Ljubanovic D, Dursun B, Lenderink AM, Edelstein CL, Holers VM. J Am Soc Nephrol. 2006 Mar;17(3):707-15. Epub 2006 Feb 8.

 

Altered renal tubular expression of the complement inhibitor Crry permits complement activation after ischemia/reperfusion. Thurman JM, Ljubanović D, Royer PA, Kraus DM, Molina H, Barry NP, Proctor G, Levi M, Holers VM. J Clin Invest. 2006 Feb;116(2):357-68. Epub 2006 Jan 26.

 

The central role of the alternative complement pathway in human disease. Thurman JM, Holers VM. J Immunol. 2006 Feb 1;176(3):1305-10. Review.

 

Acute tubular necrosis is characterized by activation of the alternative pathway of complement. Thurman JM, Lucia MS, Ljubanovic D, Holers VM. Kidney Int. 2005 Feb;67(2):524-30.

 

A novel inhibitor of the alternative complement pathway prevents antiphospholipid antibody-induced pregnancy loss in mice. Thurman JM, Kraus DM, Girardi G, Hourcade D, Kang HJ, Royer PA, Mitchell LM, Giclas PC, Salmon J, Gilkeson G, Holers VM.

Mol Immunol. 2005 Jan;42(1):87-97.

 

The alternative pathway of complement in disease: opportunities for therapeutic targeting. Holers VM, Thurman JM. Mol Immunol. 2004 Jun;41(2-3):147-52. Review.

 

Lack of a functional alternative complement pathway ameliorates ischemic acute renal failure in mice. Thurman JM, Ljubanovic D, Edelstein CL, Gilkeson GS, Holers VM.

J Immunol. 2003 Feb 1;170(3):1517-23.

 

Joshua M. Thurman, M.D.

Derek Strassheim, Ph.D.

Siranush Anna Sargsyan, Ph.D.

Brandon Renner, M.S.

Richard Fuquay, M.D.

Amanda Holland-Neidermyer, B.A.

Maria Wong, M.S.