Dr. Markus Mapara's Research

Mapara Lab Research

The research in this laboratory is primarily focused on developing new approaches to improve the outcome of patients with hematologic malignancies undergoing allogeneic hematopoietic stem cell transplantation.

1.     Role of  STAT1 in GVHD

STAT1 is the major downstream signal transducer for type I and II interferons. Our lab is focusing on the question how STAT1 regulates GVHD. Regulatory CD4+CD25+Foxp3+ T cells (Treg) have been shown to be critical regulators of immune tolerance, inflammation and autoimmunity. Given their potent suppressive effects in various preclinical models, freshly isolated or ex vivoexpanded Treg cells constitute a very attractive strategy for the treatment of various inflammatory conditions including Graft versus Host Disease (GVHD) following allogeneic blood or marrow transplantation (BMT). We have recently shown that 1) STAT1 inhibits expansion of natural Treg (nTreg) and inducible Treg (iTregex vivo and in vivo; 2) ex vivo expanded STAT1-deficient Treg cells are more resistant to apoptosis and have a higher proliferative capacity than wildtype Treg leading to enhanced ex vivo expansion; 3) ex vivoexpanded STAT1-deficient Treg cells are superior in suppressing GVHD in vivo. We are now further evaluating how STAT1  regulates homing of Treg cells to GVHD target organs and whether STAT1-silencing can be used to promote expansion of Treg cells in vivo.

In addition to the role of STAT1 in Treg cells we are working on how STAT1 affects GVL responses and host APC function following allogeneic BMT and its role in regulating tissue infiltration and destruction during the effector phase of GVHD.

2.     Inhibition of inflammatory signaling pathways for prevention and treatment of GVHD: Identification of novel molecular targets.

The major goal of this project is to identify promising molecular targets to inhibit the development of GVHD following allogeneic HSCT. We have shown that Histone Deacetylase (HDAC) Inhibitors can modulate the inflammatory response and attenuate development of GVHD following fully MHC-mismatched BMT.  Using small molecule inhibitors we are planning to identify druggable targets which could help prevent or treat GVHD. Another aspect we are pursuing in the lab is the role of anti-inflammatory endogenous lipids (e.g. Resolvins) as modulators of GVHD in murine BMT models.

3.     Regulation of Donor-Lymphocyte Infusion (DLI)-mediated GVL effects

Donor lymphocyte infusion (DLI) following allogeneic bone marrow transplantation (BMT) is a very potent form of immunotherapy and can lead to Graft versus Leukemia (GVL) effects in the absence of Graft versus Host Disease (GVHD). However, DLI-mediated GVL effects can be transient and relapse of the underlying malignancy is an important clinical problem. We have demonstrated in rodent BMT models that loss of GVL reactivity following DLI administration coincides with extinction of the alloreactive population. We are interested in determining the molecular mechanisms underlying the extinction of this alloreactive population with the goal of identifying  molecular targets to achieve sustained GVL-effects.

Lab members:

Caisheng Lu, PhD

Hui-Hui Ma, MD PhD

 

Selected Publications:

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1.     Qu Z, Fu J, Ma H, Zhou J, Jin M, Mapara MY, Grusby MJ, Xiao G.2012. PDLIM2 restricts Th1 and Th17 differentiation and prevents autoimmune disease. Cell Biosci. 2(1):23. [Epub ahead of print] PMID: 2273140

2.     Lentzsch S, O'Sullivan A, Kennedy RC, Abbas M, Dai L, Pregja SL, Burt S, Boyiadzis M, Roodman GD, Mapara MY, Agha M, Waas J, Shuai Y, Normolle D, Zonder JA Combination of bendamustine, lenalidomide, and dexamethasone (BLD) in patients with relapsed or refractory multiple myeloma is feasible and highly effective: results of phase 1/2 open-label, dose escalation study. Blood. 2012. 119(20):4608-13 PMID: 22451423

 

3.     Stenger EO, Turnquist HR, Mapara MY, Thomson AW.2012. Dendritic cells and regulation of graft-versus-host disease and graft-versus-leukemia activity. Blood. 2012. 119:5088-103. PMID: 22403259

4.     Ma HH, L. C, Ziegler J, Sepulveda A, Liu A, Okada H, Lentzsch S, Mapara MY.2011. Absence of Stat1 in donor CD4+ T cells promotes the expansion of Tregs and reduces graft-versus-host disease in mice. J Clin Invest. 121:2554-69

5.     Ma HH, Ziegler J, Li C, Sepulveda A, Bedeir, A, Grandis J, Lentzsch S, Mapara MY.2011. Sequential Activation of Inflammatory Signaling Pathways During Graft-versus-Host Disease (GVHD): Early Role for STAT1 and STAT3. Cell.Immunol. 268:37-46

6.     Li S, Pal R, Monaghan SA, Schafer P, Ouyang H, Mapara M, Galson DL, Lentzsch S.2011. IMiD immunomodulatory compounds block C/EBP{beta} translation through eIF4E down-regulation resulting in inhibition of MM. Blood. 117:5157-65. Epub 2011 Mar 9.

7.     Randhawa PS, Farasati NA, Huang Y, Mapara MY. 2011. Shapiro R Viral drug sensitivity testing using quantitative PCR: effect of tyrosine kinase inhibitors on polyomavirus BK replication. Am J Clin Pathol.134:916-20.

8.     Pal R, Janz M, Galson DL, Gries M, Li S, Johrens K, Anagnostopoulos I, Dorken B, Mapara MY, Borghesi L, Kardava L, Roodman GD, Milcarek C, Lentzsch S. 2009. C/EBP{beta} regulates transcription factors critical for proliferation and survival of multiple myeloma cells.Blood. 114:2890-8. PMID: 19717648

9.     Feng, R, Anderson, G, Xiao, G, Elliott, G, Leoni, L, Mapara, MY, Roodman, GD, and Lentzsch, S.  2007 SDX-308, a nonsteroidal anti-inflammatory agent, inhibits NF-kappaB activity, resulting in strong inhibition of osteoclast formation/activity and multiple myeloma cell growth. Blood, 109: 2130-2138. PMID:17095620

10. Mapara MY, Leng C, Kim YM, Bronson R, Lokshin A, Luster A, Sykes M. 2006. Expression of Chemokines in GVHD Target Organs Is Influenced by Conditioning and Genetic Factors and Amplified by GVHR. Biol Blood Marrow Transplant. 12:623-634. PMID:16737935

11. Leng C, Gries M, Ziegler J, Lokshin A, Mascagni P, Lentzsch S, Mapara MY. 2006. Reduction of graft-versus-host disease by histone deacetylase inhibitor suberonylanilide hydroxamic acid is associated with modulation of inflammatory cytokine milieu and involves inhibition of STAT1. Exp Hematol. 34:776-87. PMID: 16728283

12. Lentzsch S, Gries M, Janz M, Bargou R, Dorken B, Mapara MY. 2003. Macrophage inflammatory protein-1alpha (MIP-1{alpha}) triggers migration and signaling cascades mediating survival and proliferation in multiple myeloma (MM) cells. Blood. 101: 3568-3573PMID: 12506012

13. Mapara M.Y., Kim,YM, Marx JE, Sykes M 2003. DLI-mediated GVL effects in mixed chimeras established with a nonmyeloablative conditioning regimen: extinction of GVL effects following conversion to full donor chimerism.  Transplantation 76:297-305. PMID: 12883182

14. Mapara M. Y., Y.-M. Kim, S.P. Wang, R. Bronson, D.H. Sachs and M. Sykes. 2002. Donor lymphocyte infusions (DLI) mediate superior GVL effects in mixed compared to fully allogeneic chimeras: A critical role for host antigen presenting cells. Blood 100: 1903-1909. PMID: 12176915

15. Mapara, M.Y., I.J. Körner, M. Hildebrandt, R. Bargou, D. Krahl, P. Reichardt, and B. Dörken. 1997. Monitoring of Tumor cell purging after highly efficient immunomagnetic selection of CD34 cells from leukapheresis products in breast cancer patients: comparison of immunocytochemical tumor cell staining and RT-PCR. Blood 89:337 - 344.PMID: 8978310

16. Wolff, G., I.J. Körner, W. Arnold, A. Schuhmacher, B. Dörken, and M.Y.Mapara. 1998. Purging of Breast Cancer Cells by Short Term Administration of Cytosine Deaminase and 5‑Fluorocytosine Prevents Tumor Growth after Transplantation Hum Gene Ther 9:2277-84.PMID: 9794211