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Transplant Surgical Research

Kim M. Olthoff, M.D.

Dr. Olthoff's current laboratory research involves both basic science studies and human translational research and focuses on liver regeneration in the transplant setting and ischemia/reperfusion injury as outlined below. These lines of investigation are funded by multiple NIH grants and the Biesecker Center for Pediatric Liver Disease. The research is carried out in the Stemmler laboratories, collaborative Biesecker Liver Center research space in Abramson, and with the clinical research staff on 2 Dulles. We have strong collaborations with Dr. Jason Christie (CCEB), Dr. Wayne Hancock (CHOP), and Dr. Daniel Salomon (Scripps Research Institute). The laboratory personnel have published in top-ranked journals such as Nature Medicine, Hepatology, American Journal of Transplantation, Liver Transplantation and Transplantation.

 
Animal Studies
  1. Early gene expression in the liver graft in murine models of partial hepatectomy, lobar ischemia and resection, and bile duct ligation.
    1. Use of cDNA microarray, RNA protection assays, multimeric RT-PCR technology, immunopathology, small molecule and antibody therapy.
  2. Murine whole and partial liver grafts and tolerance for ischemic injury
    1. Determining minimal liver volume and molecular events in the development of “small-for-size” syndrome.
  3. Critical factors in liver regeneration and the interplay between hepatic growth and metabolism
    1. Role of IL-6, PPAR-? signaling, and growth factors in liver regeneration in the transplant setting
Human Translational Studies
  1. Regeneration and assessment of liver function in donors and recipients following partial hepatectomy and living donor transplantation.
    1. Differential gene expression in liver biopsies and peripheral blood obtained post reperfusion, determining prognostic indicators of graft function.
    2. Utilization of other molecular techniques, such as microRNA, Luminex, and RT-PCR.
    3. Funded as part of an ancillary study to the NIH A2ALL multicenter consortium studying outcomes in living donor liver transplantation.
Clinical Research
  1. Liver regeneration after LD transplantation by volumetric imaging
  2. Impact of pretransplant locoregional therapy for HCC on post-transplant outcomes
  3. Outcome of liver transplantation in older recipients
 
Research Grants
NIH/NIDDK U01-DK-062494 (Olthoff, PI)
Adult to Adult Living Donor Liver Transplant Cohort Study (A2ALL)
Penn is one of 9 centers in this multi-center trial with the primary goal of providing information on the outcomes of adult to adult living donor liver transplantation in donors and recipients.

NIH/NIDDK RO1-DK073192 (Olthoff, PI)
Regeneration in the Transplant Setting: An Ancillary Study to the A2ALL
This study is within the cooperative, multi-site A2ALL consortium, examining the mechanisms occurring in the early post-transplantation period that drive molecular networks for liver regeneration and tissue repair required for graft and patient survival in living donor and deceased donor liver transplantation.

NIH/NIAID U01 A1063589 (Shaked, PI, Olthoff, Center Co-I)
Clinical trials in organ transplantation (CTOT-3) – Correlation of donor proinflammatory mRNA profiles with early outcomes of thoracic and abdominal transplantation
This study is a prospective observational cohort designed to test the association of proinflammatory pathways of injury in lung, heart, liver and kidney allografts with immediate and short-term function as well subsequent alloimmune response. This study will profile gene expression for the characterization of innate immunity and adaptive immunity pertinent to solid organ transplantation. Dr. Olthoff directs the liver studies

NIH/NIAID U01 AI052748 (Olthoff, Site PI)
Solid Organ Transplantation in HIV: Multi-Site Study
The University of Pennsylvania is one of 16 transplant centers from across the country participating in this multi-site study investigating outcomes in kidney and liver transplantation in people with HIV.

Biesecker Center for Liver Disease – Private Grant
Models of liver regeneration and ischemia/reperfusion injury in the transplant setting
This privately funded research grant provides support for the murine studies investigating the roles of growth factors and metabolic pathways in liver regeneration.

 
Publications (selected from 100 peer reviewed publications)
  1. Olthoff KM, Rosove MH, Imagawa DK, Shackleton CR, Farmer D, Martin P, Goldstein LI, Shaked A, Busuttil RW. Adjuvant chemotherapy improves survival following liver transplantation for hepatocellular carcinoma. Ann Surg 1995 221:734-743.
  2. Olthoff KM, Judge TA, Gelman A, Chen X, Hancock WW, Turka LA, Shaked A. Adenovirus-mediated gene transfer into cold-preserved liver allografts: Survival pattern and unresponsiveness following transduction with CTLA4Ig. Nat Med 1998 4:194-200.
  3. Olthoff KM, Shaked A, Yi J, Gelman AE, Shen X, Kesmodel S, Poma SH, Krasinkas AM, Rosengard BR, Kovalovich K, DeAngelis RA, Taub R. Intrahepatic bone marrow derived cells are responsible for IL-6-induced STAT 3 activation after partial hepatectomy. Hepatology 1998 28:402A.
  4. Olthoff KM, Shen XD, Debonera F, Gao F, Aldeguer X, Gelman AE, Hiroyashu S, Furth EE, Shaked A, Taub R. Initiation of early signal transduction pathways in the liver following cold ischemia and reperfusion injury. Transplantation 1999 67(9):S559.
  5. Lehrer MS, Ruchelli E, Olthoff KM, French LE, Rook AH. Successful reversal of recalcitrant hepatic allograft rejection by photopheresis. Liver Transpl 2000 6:644-647.
  6. Zamir GA, Markmann JF, Abrams J, Macatee MR, Nunes FA, Shaked A, Olthoff KM. The fate of liver grafts declined for subjective reasons and transplanted out of a local procurement organization. Transplantation 2000 70(8):1149-1154.
  7. Debonera F, Aldeguer X, Shen X, Gelman AE, Gao F, Que X, Greenbaum LE, Furth EE, Taub R, Olthoff KM. Activation of IL-6/STAT3 and liver regeneration following transplantation. J Surg Res 2001 96:289-295.
  8. Zamir G, Gelman A, Debonera F, Hardwigsen J,Que X, Aldeguer X, Martin M, Shaked A, Olthoff K. Modified AdCTLA-4 vector blocks alloimmune response in-vitro. J Surg Res 2001 97:155-158.
  9. Singer AL, Olthoff KM, Kim H, Rand E, Zamir G, Shaked A. The role of plasmapheresis in the management of acute hepatic failure in the pediatric population. Ann Surg 2001 234: 418-424.
  10. Olthoff KM, Gelman AE, Zamir GA, Debonera F, Krasinkas AM, Shen X, Gao F, Shaked A. Pattern of alloimmune response in second same donor allografts after induction of tolerance using CTLA4Ig. Transplantation 2001 Dec 27:72(12):1952-6.
  11. Aldeguer X, Debonera F, Shaked A, Krasinkas AM, Que X, Zamir GA, Hiroyasu S, Kovalovich KK, Taub R, Olthoff KM. Interleukin-6 from cells of bone marrow origin is required for normal liver regeneration. Hepatology 2002 Jan:35(1):40-8.
  12. Debonera F, Krasinkas A, Aldequer X, Que X, Gelman A, Shaked A, Olthoff K. Dexamethasone inhibits the early regenerative response of the rat liver after cold preservation and transplantation. Hepatology 2003 Dec:38(6):1563-1572.
  13. Que X, Debonera F, Xie J, Furth EE, Aldeguer X, Gelman AE, Olthoff KM. Pattern of ischemia reperfusion injury in a mouse orthotopic liver transplant model J Surg Res 2004116:262-268.
  14. Shetty K, Timmins K, Brensinger C, Furth EE, Rattan S, Sun W, Rosen M, Soulen M, Shaked A, Reddy KR, Olthoff KM. Liver transplantation for hepatocellular carcinoma: Validation of present selection criteria in predicting outcome. Liver Transpl 2004 10(7):911-918.
  15. Abt PL, Mange K, Olthoff KM, Reddy R, Shaked A. Allograft survival following adult to adult living donor liver transplantation. Am J Transplant 2004;4(8):1302-7.
  16. Abt PL, Rapaport-Kelz R, Desai N, Frank A, Sonnad S, Rand E, Markmann JF, Shaked A, Olthoff KM. Survival among pediatric liver transplant recipients: Impact of segmental grafts. Liver Transpl 2004 10(10):1287.
  17. Olthoff KM, Brown RS Jr., Delmonico FL, Freeman RB, McDiarmid SV, Merion RM, Millis JM, Roberts JP, Shaked A, Wiesner RH, Lucey MR. Summary report of a national conference: Evolving concepts in liver allocation, the MELD and PELD era. Liver Transpl. 2004 10 Suppl 10:A6.
  18. Makuuchi M, Miller CM, Olthoff K, Schwartz M. Adult-adult living donor liver transplantation. J Gastrointest Surg 2004 8(3):303-12.
  19. Hanto DW, Fishbein TM, Pinson CW, Olthoff KM, Shiffman ML, Punch JD, Goodrich NP. Liver and intestine transplantation: Summary Analysis, 1994-2003. Am J. Transplant 2005 5(Part 2)916-933.
  20. Debonera F, Wang G, Xie J, Gelman A, LeClair C, Xin D, Shaked A, Olthoff KM. Severe preservation injury induces II-6/STAT3 activation with lack of cell cycle progression after partial liver graft transplantation. Am J Transplant 2004 Dec:4(12):1964-71.
  21. Olthoff KM, Merion RM, Ghobrial RM, Abecassis MM, Fair JH, Fisher RA, Freise CE, Kam I, Pruett TL, Everhart JE, Hulbert-Shearon TE, Gillespie, BW, Edmond JC, A2ALL Study Group. Outcomes of 385 Adult-to-Adult Living Donor Liver Transplant Recipients. Ann Surg 2005 242(3):1-12.
  22. Elstrom RL, Andreadis C, Aqui NA, Ahya VN, Bloom RD, Brozena SC, Olthoff KM, Schuster SJ, Nasta SD, Stadtmauer EA, Tsai DE. Treatment of PTLD with rituximab or chemotherapy. Am J Transplant 2006 Mar;6(3):569-76.
  23. Xie JF, Wang G, Debonera F, Han R, Dorf ME, Hancock W, Olthoff KM. Selective neutralization of the chemokine TCA3 reduces the increased injury of partial versus whole liver transplants induced by cold preservation. Transplantation 2006 Dec 15;82(11):1501-9.
  24. Fisher RA, Kulik LM, Freise CE, Lok ASF, Shearon TH, Brown Jr. RS, Ghobrial RM, Fair JH, Olthoff KM, Kam I, Berg CL, A2ALL Study Group. Hepatocellular carcinoma recurrence and death following living and deceased donor liver transplantation: The A2All Study. Am J Transplant 2007 Jun;7(6):1601-8.
  25. Ghobrial RM, Freise CE, Trotter JF, Tong L, Ojo AO, Fair JH, Fisher RA, Kinkhabwala MM, Koffron AJ, Pruett TL,Olthoff KM, A2ALL Study Group. Donor morbidity and mortality of adult-to-adult living donor liver transplantation. (Submitted for publication Am J Transplant 2007).
  26. Roland ME, Barin B, Carlson L, Frassetto LA, Terrault NA, Hirose R, Freise CE, Benet LZ, Ascher NL, Roberts JP, Murphy B, Keller MJ, Olthoff KM, Blumberg EA, Brayman KL, Bartlett ST, Davis CE, McCune JM, Bredt BM, Stablein DM, Stock PG. HIV-Infected liver and kidney transplant recipients: 1- and 3- year outcomes. Am J
    Transplant 2008 8:355-365.
  27. Nakamoto N, Kaplan DE, Coleclough J, Li Y, Kaminski M, Shaked A, Olthoff KM, Gostick E, Price DA, Freeman GJ, Wherry EJ, Chang K-M. Functional restoration of HCV-specific CD8 T-cells by PD1 blockage is defined by PD1 expression and compartmentalization. Gastroenterology 2008 134(7):1927-37.
  28. Bahirwani R, Campbell M, Siropaides T, Markmann J, Olthoff KM, Shaked A, Bloom R, Reddy R. Transplantation: Impact of pre-transplant renal insufficiency. Liver Transpl 2008 14:665-71.
  29. Read A, Merion RM, Roberts JP, Klintmalm GB, Abecassis MM, Olthoff KM, Langnas AN. The declaration of Istanbul: review and commentary by the American Society of Transplant Surgeons Ethics Committee and Executive Committee. Am J Transplant 2009 Nov;9(11):2466-9.
  30. Shiley KT, Gasink LB, Barton TD, Pfeiffenberger P, Olthoff KM, Blumberg EA. Increased incidence of cytomegalovirus infection in high-risk liver transplant recipients receiving valganciclovir prophylaxis versus ganciclovir prophylaxis. Liver Transpl 2009 Aug;15(8):963-8.
  31. Marin HL, Furth EE, Olthoff K, Shaked A, Soulen MC. Histopathologic outcome of neoadjuvant image-guided therapy of hepatocellular carcinoma. J Gastrointestin Liver Dis 2009 June;18(2):169-76.
  32. Abecassis MM, Burke R, Klintmalm GB, Matas J, Merion RM, Millman D, Olthoff K, Roberts JP; American Society of Transplant Surgeons. American society of transplant surgeons transplant center outcomes requirements—a threat to innovation. Am J Transplant 2009 Jun;9(6):1279-86.
  33. deJonge J, Kurian S, Shaked A, Reddy KR, Hancock W, Salomon DR, Olthoff KM. Unique early gene expression patterns in human adult-to-adult living donor liver grafts compared to deceased donor grafts. Am J Transplant 2009 Apr;9(4):758-72.
  34. Nakamoto N, Cho H, Shaked A, Olthoff KM, Valiga ME, Kaminski M, Gostick E, Price DA, Freeman GJ, Wherry EJ, Chang KM. Synergistic reversal of intrahepatic HCV-specific CD8 T cell exhaustion by combined PD-1/CTLA-4 blockage. PLoS Pathog 2009 Feb;5(2):e1000313.
  35. Hoffman SA, Wang L, Shah CV, Ahya VN, Pochettion A, Olthoff K, Shaked A, Wille K, Lama VN, Milstone A, Ware LB, Orens J, Weinacker A, Demissie E, Bellamy S, Kawut SM, Hancock WW, Christie JD, Lung Transplant Outcomes Group. Plasma cytokines and chemokines in primary graft dysfunction post-lung transplantation. Am J Transplant 2009:Feb;9(2):359-96.
Recent Invited Papers/Editorials:
  1. Olthoff KM. Hepatic regeneration in living donor liver transplantation. Liver Transplantation 2003:9(10):S35-S41.
  2. Olthoff KM, Reddy KR. First, Do No Harm: The question of liver biopsy in living liver donors. Liver Transplantation 2008;14:420-422.
  3. Olthoff KM. Small size and disease severity in living donation: a difficult match. Liver Transplant 2009 May;15(5):457-9.


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