Jarrod Dudakov, PhD

Senior Research Scientist

Jarrod Dudakov, PhD

Senior Research Scientist

Senior Research Scientist, van den Brink Laboratory Australian National Health and Medical Research Council CJ Martin Postdoctoral Research Fellow Monash University, Australia

Lab Phone

646-888-2317

Regeneration of the thymus is a critical function that allows for renewal of immune competence following stress, infection or immunodepletion caused by cytoreductive chemo- or radiation therapy. The mechanisms governing this regeneration remain poorly understood. However, thymic renewal in all (but particularly in adult) patients can be a prolonged process that significantly impairs the recovery of adaptive immunity following cytoreductive therapy and subsequently leads to an increase in opportunistic infections and higher treatment-associated morbidity and mortality. Hence one of the most significant clinical challenges is the need for rapid regeneration of thymopoiesis following induced immunodepletion and transplantation. Understanding the processes involved in endogenous thymic repair will allow for the clinical exploitation of strategies for therapeutic thymic regeneration.

We have recently identified an endogenous network of thymic regeneration whereby 1) injury to the thymus, and in particular the depletion of CD4+CD8+ double positive (DP) thymocytes triggers 2) upregulation of Interleukin-23 (IL-23) by a subset of thymic dendritic cells (tDCs), which induces 3) the production of IL-22 by a type of innate lymphoid cells called lymphoid tissue-inducer cells (LTi). This cascade of events leads to IL-22-mediated regeneration of the supporting thymic epithelial cell (TEC) microenvironment and, ultimately, to rejuvenation of thymopoiesis.

Several interesting areas of future study have arisen from this initial discovery including 1) exploring the mechanisms of thymic damage that trigger this regenerative network, 2) the clinical translation of IL-22 as a potential regenerative therapy to boost immune function and 3) the role of IL-22 in age-related thymic involution.

Awards:

2013: American Society for Hematology (ASH) Scholar Award

2013: Memorial Sloan-Kettering Cancer Center (MSKCC) Postdoctoral Research Award

2013: NIH (NCI) K99/R00 Pathway to Independence Award

Education

Monash University, Melbourne, Australia

Publications

Selected Publications


  1. Chidgey AP, Dudakov JA, Seach N and Boyd RL. (2007) Impact of niche aging on thymic regeneration and immune reconstitution. Seminars in Immunology. 19: 331-40

  2. Hince M, Sakkal S, Vlahos K, Dudakov J, Boyd, R and Chidgey A. (2008) The role of sex steroids and gonadectomy in the control of thymic involution. Cellular Immunology. 252:122-138

  3. Chidgey AP, Seach NS, Dudakov JA, Hammett MV and Boyd RL. (2008) Strategies for reconstituting and boosting T cell-based immunity following haematopoietic stem cell transplantation: pre-clinical and clinical approaches. Seminars in Immunopathology. 30:457-477

  4. Goldberg GL, King CG, Suh DY, Smith OM, Ajodan RS, Dudakov JA, Chidgey AP, Boyd RL and van den Brink MRM (2009). Leutenizing Hormone Releasing Hormone enhances T cell recovery following allogeneic bone marrow transplantation. Journal of Immunology. 182:5846-5854

  5. Dudakov JA*, Goldberg GL*, Reiseger J, Chidgey AP and Boyd RL. Withdrawal of sex steroids reverses age- and chemotherapy-related defects in bone marrow lymphopoiesis. (2009) Journal of Immunology. 182:6247-6260 (* - contributed equally)

  6. Dudakov JA, Goldberg GL, Reiseger JJ, Vahos K, Chidgey AP and Boyd RL.  Sex steroid ablation enhances hematopoietic recovery following cytotoxic antineoplastic therapy in aged mice. (2009) Journal of Immunology, 183:7084-7094

  7. Heng TSP, Dudakov JA, Khong DMP, Chidgey AP and Boyd RL. Stem Cells – Meet Immunity. (2009) Journal of Molecular Medicine. 187:1061-1069

  8. Goldberg GL*, Dudakov JA*, Seach N, Reiseger J, Ueno T, Vlahos K, Hammett M, Young L, Chidgey AP and Boyd RL. Sex steroid ablation enhances thymic recovery following anti-neoplastic therapy in young mice. (2010) Journal of Immunology 184:6014-6024. * - contributed equally

  9. Dudakov JA, Khong DMP, Boyd RL and Chidgey AP. Feeding the fire: the role of defective bone marrow function on exacerbating thymic involution. (2010) Trends in Immunology, 31:191-198

  10. Hanash AM, Kappel LW, Yim NL, Nejat RA, Goldberg GL, Smith OM, Rao UK, Dykstra L, Na IK, Holland AM, Dudakov JA, Liu C, Murphy GF, Leonard WJ, Heller G and van den Brink MR. Abrogation of donor T cell IL-21 signaling leads to tissue-specific modulations of immunity and separation of GVHD from GVL. (2011) Blood. 118:446-455

  11. Calder AE, Hince MN, Dudakov JA, Chidgey AP and Boyd RL. Thymic Involution: Where endocrinology meets immunology.  (2011) Neuroimmunomodulation, 18:281-289

  12. Dudakov JA and van den Brink MRM. Greater than the sum of their parts: Combination strategies for immune regeneration following allogeneic hematopoietic stem cell transplantation. (2011). Best Pract. Res. Clin. Haematol. 24:467-476.

  13. Dudakov JA and van den Brink MRM. Supply-side economics finds the thymus. (2011). Blood. 118:1715-1716.

  14. Dudakov JA, Hanash AM, Jenq RR, Young LF, Ghosh A, Singer NV, West ML, Smith OM, Holland AM, Tsai JJ, Boyd RL and van den Brink MRM. Interleukin-22 drives endogenous thymic regeneration in mice. (2012) Science. 336:91-95. Published online 1 March 2012. (DOI:10.1126/science.1218004)

    • Perspective: Bhandoola and Artis. Rebuilding the thymus. (2012) Science 336:40-41
    • Cell Select: Regenerative medicine: A cytokine for immune recovery. Cell 149:727-729
    • F1000 evaluation: Perruche S, Saas P: 2012. F1000.com/14218962#eval15732067
    • F1000 evaluation: Pawelec G: 2012. F1000.com/14218962#eval790402834
    • F1000 evaluation: Bosselut R: 2012. F1000.com/14218962#eval791802891
  15. Jenq R, Ubeda C, Taur Y, Menezes CC, Khanin R, Dudakov JA, Liu C, West ML, Singer NV, Equinda MJ, Gobourne A, Lipuma L, Young LF, Smith OM, Ghosh A, Hanash AM, Goldberg JD, Aoyama K, Blazar BR, Pamer EG and van den Brink MRM. Regulation of intestinal inflammation by intestinal microbiota following allogeneic bone marrow transplantation. (2012) J. Exp. Med. 209:903-911. Published online 30th April (doi:10.1084/jem.20112408).

  16. Hanash AM, Dudakov JA, Hua G, O’Connor MH, Young LF, Singer NV, West ML, Jenq RR, Holland AM, Kappel LW, Ghosh A, Tsai JJ, Rao UK, Yim NL, Smith OM, Velardi E, Hawryluk EB, Murphy GF, Liu C, Fouser LA, Kolesnick R, Blazar BR and van den Brink MRM. Interleukin-22 Protects Intestinal Stem Cells from Immune-Mediated Tissue Damage and Regulates Sensitivity to Graft versus Host Disease. (2012) Immunity. 37:339-350.

    • Preview: Diefenbach A. Interleukin-22, the Guardian of the Intestinal Stem Cell Niche? (2012) Immunity 37:196-198
  17. Holland AM, Zakrzewski JL, Tsai JJ, Hanash AM, Dudakov JA, Smith OM, West ML, Singer NV, Brill J, Sun JC and van den Brink MRM. Adoptive T cell precursor therapy enhances thymus-independent development of functional mature T cells. (2012) J. Clin. Invest. 122:4716-4726. Published online 21st November, 2012.

  18. Hartrampf S*, Dudakov JA*, Johnson LK, Smith OM, Tsai JJ, Singer NV, West ML, Hanash AM, Albert MH, Liu BF, Toth M and van den Brink MRM. The central nervous system is a target organ in murine acute graft versus host disease. (2013). Blood 121:1906-1910. Published online January 8th, 2013. * - contributed equally.

  19. Tsai JJ, Dudakov JA, Takahashi K, Shieh JH, Singer NV, West ML, Smith OM, Young LF, Holland AM, Shono Y, Ghosh A, Tran HT, Moore MA and van den Brink MRM. Nrf2 regulates hematopoietic stem cell function. (2013) Nat Cell Biol. 15:309-316. Published online February 24th, 2013.

  20. Ferrando-Martinez S, Ruiz-Mateos E, Dudakov JA, Velardi E, Grillari J, Kreill DP, Munoz-Fernandez MA, van den Brink MRM and Leal M. WNT signaling suppression in the senescent human thymus. (2014). J Gerontol A Biol Sci Med Sci. Mar 30 [Epub ahead of print]

  21. Velardi E, Tsai JJ, Holland AM, Wertheimer T, Yu VWC, Zakrzewski JL, Tuckett AZ, Singer NV, West ML, Smith OM, Young LF, Kreines FM, Levy ER, Boyd RL, Scadden DT, Dudakov JA* and van den Brink MRM*. Sex steroid blockade enhances thymopoiesis by modulating Notch signaling. (2014). J. Exp. Med. 211:2341-2349. * Co-senior author

  22. Khong DKM*, Dudakov JA*, Hammett MV, Goldberg GL, Ueno T, Jurblum MI, Spyroglou L, Young LF, van den Brink MRM, Boyd RL, and Chidgey AP. Enhanced hematopoietic stem cell function mediates immune regeneration following sex steroid blockade. (In Press) Stem Cell Reports. * co-first author

  23. Dudakov JA, Hanash AM and van den Brink MRM. Interleukin-22 and Epithelial Function. (In Press). Annual Rev. Immunol.

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