Photo of David H. Sachs,  MD

David H. Sachs, MD

Massachusetts General Hospital

Massachusetts General Hospital
Phone: (617) 726-4065
Fax: (617) 726-4067

David H. Sachs, MD

Massachusetts General Hospital

EDUCATIONAL TITLES

  • Paul S. Russell/Warner Lambert Professor of Surgery, Surgery, Harvard Medical School
  • Director, Transplantation Biology Research Center Laboratories, Center for Transplantation Sciences, Massachusetts General Hospital

DF/HCC PROGRAM AFFILIATION

Research Abstract

Our laboratory utilizes partially inbred miniature swine as a large animal pre-clinical model and as potential donors for organ xenotransplantation. Three herds of miniature swine homozygous for different sets of histocompatibility antigens at the major histocompatibility complex (MHC) have been developed by the principal investigator over the past 30 years. These animals show many similarities to humans both immunologically and physiologically and are of similar size to humans, facilitating their potential use as xenograft donors. In addition, five different intra-MHC recombinants have been isolated and bred to homozygosity, making this the only large animal model in which immunogenetic studies of the MHC and its role in transplantation can be performed reproducibly. Our current projects include: 1) Assessment of the effect of selective MHC matching on the survival of organ and tissue transplants: Studies are carried out in vivo and in vitro assessing the mechanism of rejection and induction of transplantation tolerance across selective MHC barriers; 2) Production and characterization of monoclonal antibodies reactive with subsets of pig lymphocytes; 3) Bone marrow transplants in miniature swine: The effect of treatment regimens to mitigate Graft-versus-Host disease (GVHD) and the use of bone marrow transplantation as a means for inducing specific transplantation tolerance across MHC barriers are being studied; 4) Studies of porcine to primate xenografts: Attempts are under way to extend our previous studies on induction of specific tolerance across concordant species barriers (rat to mouse and baboon to monkey) to the discordant xenograft system (pig to baboon). Induction of tolerance is tested by organ xenografts. Major collaborative studies within the TBRC and between the TBRC and the Transplant Unit of the Surgery Department are carried out.

Publications

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  • Wang Z, Wei M, Zhang H, Chen H, Germana S, Huang CA, Madsen JC, Sachs DH, Wang Z. Diphtheria-toxin based anti-human CCR4 immunotoxin for targeting human CCR4(+) cells in vivo. Mol Oncol 2015. PubMed
  • Madariaga ML, Michel SG, La Muraglia GM, Sihag S, Leonard DA, Farkash EA, Colvin RB, Cetrulo CL, Huang CA, Sachs DH, Madsen JC, Allan JS. Recipient-matching of Passenger Leukocytes Prolongs Survival of Donor Lung Allografts in Miniature Swine. Transplantation 2015. PubMed
  • Mathes DW, Solari MG, Gazelle GS, Butler PE, Wu A, Nazzal A, Nielsen GP, Huang CA, Sachs DH, Lee WP, Randolph MA. Stable mixed hematopoietic chimerism permits tolerance of vascularized composite allografts across a full major histocompatibility mismatch in swine. Transpl Int 2014; 27:1086-96. PubMed
  • Wei M, Marino J, Trowell A, Zhang H, Stromp Peraino J, Rajasekera PV, Madsen JC, Sachs DH, Huang CA, Benichou G, Wang Z. Diphtheria toxin-based recombinant murine IL-2 fusion toxin for depleting murine regulatory T cells in vivo. Protein Eng. Des. Sel. 2014; 27:289-95. PubMed
  • Peraino JS, Zhang H, Rajasekera PV, Wei M, Madsen JC, Sachs DH, Huang CA, Wang Z. Diphtheria toxin-based bivalent human IL-2 fusion toxin with improved efficacy for targeting human CD25(+) cells. J Immunol Methods 2014; 405:57-66. PubMed
  • Tena A, Sachs DH. Stem cells: Immunology and immunomodulation. Dev Ophthalmol 2014; 53:122-32. PubMed
  • Sachs DH, Kawai T, Sykes M. Induction of tolerance through mixed chimerism. Cold Spring Harb Perspect Med 2014; 4:a015529. PubMed
  • Peraino JS, Schenk M, Li G, Zhang H, Farkash EA, Sachs DH, Huang CA, Duran-Struuck R, Wang Z. Development of a diphtheria toxin-based recombinant porcine IL-2 fusion toxin for depleting porcine CD25+ cells. J Immunol Methods 2013; 398-399:33-43. PubMed
  • Wamala I, Matar AJ, Farkash E, Wang Z, Huang CA, Sachs DH. Recombinant anti-monkey CD3 immunotoxin depletes peripheral lymph node T lymphocytes more effectively than rabbit anti-thymocyte globulin in naïve baboons. Transpl Immunol 2013; 29:60-3. PubMed
  • Peraino JS, Schenk M, Zhang H, Li G, Hermanrud CE, Neville DM, Sachs DH, Huang CA, Duran-Struuck R, Wang Z. A truncated diphtheria toxin based recombinant porcine CTLA-4 fusion toxin. J Immunol Methods 2013. PubMed
  • Kawai T, Sachs DH, Sykes M, Cosimi AB, . HLA-mismatched renal transplantation without maintenance immunosuppression. N Engl J Med 2013; 368:1850-2. PubMed
  • Shimatsu Y, Yamada K, Horii W, Hirakata A, Sakamoto Y, Waki S, Sano J, Saitoh T, Sahara H, Shimizu A, Yazawa H, Sachs DH, Nunoya T. Production of cloned NIBS (Nippon Institute for Biological Science) and α-1, 3-galactosyltransferase knockout MGH miniature pigs by somatic cell nuclear transfer using the NIBS breed as surrogates. Xenotransplantation 2014. PubMed
  • Weiner J, Scalea J, Ishikawa Y, Okumi M, Griesemer A, Hirakata A, Etter J, Gillon B, Moran S, Shimizu A, Yamada K, Sachs DH. Tolerogenicity of donor major histocompatibility complex-matched skin grafts in previously tolerant Massachusetts general hospital miniature swine. Transplantation 2012; 94:1192-9. PubMed
  • Matar AJ, Crepeau RL, Pathiraja V, Robson S, Fishman JA, Spitzer TR, Sachs DH, Huang CA, Duran-Struuck R. Effects of mobilization regimens in donors on outcomes of hematopoietic cell transplantation in miniature Swine. Comp Med 2013; 62:487-94. PubMed
  • Duran-Struuck R, Matar A, Crepeau R, Gusha A, Schenk M, Hanekamp I, Pathiraja V, Spitzer TR, Sachs DH, Huang CA. Lack of antidonor alloantibody does not indicate lack of immune sensitization: studies of graft loss in a haploidentical hematopoietic cell transplantation swine model. Biol Blood Marrow Transplant 2012; 18:1629-37. PubMed
  • Matar AJ, Pathiraja V, Wang Z, Duran-Struuck R, Gusha A, Crepeau R, Tasaki M, Sachs DH, Huang CA. Effect of pre-existing anti-diphtheria toxin antibodies on T cell depletion levels following diphtheria toxin-based recombinant anti-monkey CD3 immunotoxin treatment. Transpl Immunol 2012; 27:52-4. PubMed
  • Crepeau R, Matar A, Spitzer TR, Robson S, Pathiraja V, Sachs DH, Huang CA, Duran-Struuck R. Edema and tetraparesis in a miniature pig after allogeneic hematopoietic cell transplantation. Comp Med 2012; 62:298-302. PubMed
  • Tena A, Vallabhajosyula P, Hawley RJ, Griesemer A, Yamada K, Sachs DH. Quantification of baboon thymopoiesis in porcine thymokidney xenografts by the signal-joining T-cell receptor excision circle assay. Transplantation 2011; 91:639-44. PubMed
  • Spitzer TR, Sykes M, Tolkoff-Rubin N, Kawai T, McAfee SL, Dey BR, Ballen K, Delmonico F, Saidman S, Sachs DH, Cosimi AB. Long-term follow-up of recipients of combined human leukocyte antigen-matched bone marrow and kidney transplantation for multiple myeloma with end-stage renal disease. Transplantation 2011; 91:672-6. PubMed
  • LoCascio SA, Morokata T, Chittenden M, Preffer FI, Dombkowski DM, Andreola G, Crisalli K, Kawai T, Saidman SL, Spitzer TR, Tolkoff-Rubin N, Cosimi AB, Sachs DH, Sykes M. Mixed chimerism, lymphocyte recovery, and evidence for early donor-specific unresponsiveness in patients receiving combined kidney and bone marrow transplantation to induce tolerance. Transplantation 2010; 90:1607-15. PubMed
  • Hirakata A, Okumi M, Griesemer AD, Shimizu A, Nobori S, Tena A, Moran S, Arn S, Boyd RL, Sachs DH, Yamada K. Reversal of age-related thymic involution by an LHRH agonist in miniature swine. Transpl Immunol 2010; 24:76-81. PubMed
  • Lutton BV, Cho PS, Hirsh EL, Ferguson KK, Teague AG, Hanekamp JS, Chi N, Goldman SN, Messina DJ, Houser S, Yeap BY, Popma SH, Sachs DH, Huang CA. Approaches to avoid immune responses induced by repeated subcutaneous injections of allogeneic umbilical cord tissue-derived cells. Transplantation 2011; 90:494-501. PubMed
  • Duran-Struuck R, Cho PS, Teague AG, Fishman B, Fishman AS, Hanekamp JS, Moran SG, Wikiel KJ, Ferguson KK, Lo DP, Duggan M, Arn JS, Billiter B, Horner B, Houser S, Yeap BY, Westmoreland SV, Spitzer TR, McMorrow IM, Sachs DH, Bronson RT, Huang CA. Myelogenous leukemia in adult inbred MHC-defined miniature swine: A model for human myeloid leukemias. 2010; 135:243-56. PubMed
  • Nadazdin O, Abrahamian G, Boskovic S, Smith RN, Schoenfeld DA, Madsen JC, Colvin RB, Sachs DH, Cosimi AB, Kawai T. Stem Cell Mobilization and Collection for Induction of Mixed Chimerism and Renal Allograft Tolerance in Cynomolgus Monkeys. J Surg Res 2010. PubMed
  • Weiner J, Yamada K, Ishikawa Y, Moran S, Etter J, Shimizu A, Smith RN, Sachs DH. Prolonged survival of GalT-KO swine skin on baboons. Xenotransplantation 2010; 17:147-52. PubMed
  • Mulder A, Kardol MJ, Arn JS, Eijsink C, Franke ME, Schreuder GM, Haasnoot GW, Doxiadis II, Sachs DH, Smith DM, Claas FH. Human monoclonal HLA antibodies reveal interspecies crossreactive swine MHC class I epitopes relevant for xenotransplantation. Mol Immunol 2010; 47:809-15. PubMed
  • Hanekamp JS, Okumi M, Tena A, Arn S, Yamada K, Sachs DH. Cytoplasmic inheritance of transplantation antigens in animals produced by nuclear transfer. Transplantation 2009; 88:30-7. PubMed
  • Meltzer AJ,Weiss MJ,Veillette GR,Sahara H,Ng CY,Cochrane ME,Houser SL,Sachs DH,Rosengard BR,Madsen JC,Wain JC,Allan JS. Repetitive gastric aspiration leads to augmented indirect allorecognition after lung transplantation in miniature swine. Transplantation 2008; 86:1824-9. PubMed
  • Shimizu A, Hisashi Y, Kuwaki K, Tseng YL, Dor FJ, Houser SL, Robson SC, Schuurman HJ, Cooper DK, Sachs DH, Yamada K, Colvin RB. Thrombotic Microangiopathy Associated with Humoral Rejection of Cardiac Xenografts from {alpha}1,3-Galactosyltransferase Gene-Knockout Pigs in Baboons. Am J Pathol 2008; 172:1471-81. PubMed
  • Okumi M, Fishbein JM, Griesemer AD, Gianello PR, Hirakata A, Nobori S, Moran S, Samelson-Jones E, Shimizu A, Sachs DH, Yamada K. Role of persistence of antigen and indirect recognition in the maintenance of tolerance to renal allografts. Transplantation 2008; 85:270-80. PubMed
  • Kawai T, Cosimi AB, Spitzer TR, Tolkoff-Rubin N, Suthanthiran M, Saidman SL, Shaffer J, Preffer FI, Ding R, Sharma V, Fishman JA, Dey B, Ko DS, Hertl M, Goes NB, Wong W, Williams WW, Colvin RB, Sykes M, Sachs DH. HLA-mismatched renal transplantation without maintenance immunosuppression. N Engl J Med 2008; 358:353-61. PubMed
  • Cho PS, Messina DJ, Hirsh EL, Chi N, Goldman SN, Lo DP, Harris IR, Popma SH, Sachs DH, Huang CA. Immunogenicity of umbilical cord tissue derived cells. Blood 2007; 111:430-8. PubMed
  • Cho PS, Lo DP, Wikiel KJ, Rowland HC, Coburn RC, McMorrow IM, Goodrich JG, Arn JS, Billiter RA, Houser SL, Shimizu A, Yang YG, Sachs DH, Huang CA. Establishment of transplantable porcine tumor cell lines derived from MHC-inbred miniature swine. Blood 2007; 110:3996-4004. PubMed
  • Kozlowski LT, Giovino GA, Edwards B, Difranza J, Foulds J, Hurt R, Niaura R, Sachs DP, Selby P, Dollar KM, Bowen D, Cummings KM, Counts M, Fox B, Sweanor D, Ahern F. Advice on using over-the-counter nicotine replacement therapy-patch, gum, or lozenge-to quit smoking. Addict Behav 2007; 32:2140-50. PubMed
  • Hongo D, Hadidi S, Damrauer S, Garrigue V, Kraft D, Sachs DH, Nikolic B, Sykes M. Porcine thymic grafts protect human thymocytes from HIV-1-induced destruction. J Infect Dis 2007; 196:900-10. PubMed
  • Sachs DH, Yamada K, Robson SC, Fishman JA, Shimizu A, Colvin RB, Sykes M. GalT-KO pigs: is the cup half empty or half full? Transplantation 2007; 84:12-4. PubMed
  • Shaffer J, Villard J, Means TK, Alexander S, Dombkowski D, Dey BR, McAfee S, Ballen KK, Saidman S, Preffer FI, Sachs DH, Spitzer TR, Sykes M. Regulatory T-cell recovery in recipients of haploidentical nonmyeloablative hematopoietic cell transplantation with a humanized anti-CD2 mAb, MEDI-507, with or without fludarabine. Exp Hematol 2007; 35:1140-52. PubMed
  • Dey BR, Shaffer J, Yee AJ, McAfee S, Caron M, Power K, Ting DT, Colby C, Preffer F, Ballen K, Attar E, Saidman S, Tarbell N, Sachs D, Sykes M, Spitzer TR. Comparison of outcomes after transplantation of peripheral blood stem cells versus bone marrow following an identical nonmyeloablative conditioning regimen. Bone Marrow Transplant 2007; 40:19-27. PubMed
  • Koyama I, Nadazdin O, Boskovic S, Ochiai T, Smith RN, Sykes M, Sogawa H, Murakami T, Strom TB, Colvin RB, Sachs DH, Benichou G, Cosimi AB, Kawai T. Depletion of CD8 memory T cells for induction of tolerance of a previously transplanted kidney allograft. Am J Transplant 2007; 7:1055-61. PubMed
  • Papeta N, Chen T, Vianello F, Gererty L, Malik A, Mok YT, Tharp WG, Bagley J, Zhao G, Stevceva L, Yoon V, Sykes M, Sachs D, Iacomini J, Poznansky MC. Long-term survival of transplanted allogeneic cells engineered to express a T cell chemorepellent. Transplantation 2007; 83:174-83. PubMed
  • Horner BM, Cina RA, Wikiel KJ, Lima B, Ghazi A, Lo DP, Yamada K, Sachs DH, Huang CA. Predictors of organ allograft tolerance following hematopoietic cell transplantation. Am J Transplant 2007; 6:2894-902. PubMed
  • Fudaba Y, Spitzer TR, Shaffer J, Kawai T, Fehr T, Delmonico F, Preffer F, Tolkoff-Rubin N, Dey BR, Saidman SL, Kraus A, Bonnefoix T, McAfee S, Power K, Kattleman K, Colvin RB, Sachs DH, Cosimi AB, Sykes M. Myeloma Responses and Tolerance Following Combined Kidney and Nonmyeloablative Marrow Transplantation: In Vivo and In Vitro Analyses. Am J Transplant 2006; 6:2121-33. PubMed
  • Peraino JS, Hermanrud CE, Springett L, Zhang H, Li G, Srinivasan S, Gusha A, Sachs DH, Huang CA, Wang Z. Expression and characterization of recombinant soluble porcine CD3 ectodomain molecules: mapping the epitope of an anti-porcine CD3 monoclonal antibody 898H2-6-15. Cell Immunol 2012; 276:162-7. PubMed
  • Huang CA, Fuchimoto Y, Scheier-Dolberg R, Murphy MC, Neville DM, Sachs DH. Stable mixed chimerism and tolerance using a nonmyeloablative preparative regimen in a large-animal model. J Clin Invest 2000; 105:173-81. PubMed
  • Liang F, Wamala I, Scalea J, Tena A, Cormack T, Pratts S, Duran-Struuck R, Elias N, Hertl M, Huang CA, Sachs DH. Increased levels of anti-non-Gal IgG following pig-to-baboon bone marrow transplantation correlate with failure of engraftment. Xenotransplantation 2013; 20:458-68. PubMed
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