Our Labs
Research in the Korngold Lab
Immunobiology of Graft-versus-Host Disease (GVHD)
My initial work with Dr. Jonathan Sprent and in continued collaboration afterward focused on the role of allogeneic donor T cells in the etiology of GVHD across minor histocompatibility barriers. In the late 1970s, it was unclear what caused this disease in MHC-matched sibling transplants. In developing a series of novel murine models for GVHD, we provided the evidence needed to support the use of T-cell depletion to prevent GVHD in the clinical situation. The 1978 Journal of Experimental Medicine article was recognized in 2008 as a “classic” paper and one of the top ten most cited articles in this publication for the previous 30-year period. The “Korngold/ Sprent B10.BR<->CBA model for GVHD” became a mainstay of numerous future studies in the field. Unfortunately, although T-cell depletion in the clinical transplant situation proved successful over the next decade in preventing GVHD, it did not adequately address the problem of tumor relapse, and the development of optimal approaches to separate out GVHD responses from graft-versus-tumor (GVT) effects is still under study.
Korngold R, Sprent J: Lethal graft-versus-host disease following bone marrow transplantation across minor histocompatibility barriers in mice. Prevention by removing mature T cells from marrow. J. Exp. Med. 148: 1687-1698, 1978.
Korngold R, Sprent J: Selection of cytotoxic T-cell precursors specific for minor histocompatibility determinants. I. Negative selection across H-2 barriers induced with disrupted cells but not with glutaraldehyde-treated cells: Evidence for antigen-processing. J. Exp. Med. 151: 314-327, 1980.
Korngold R, Sprent J: Negative selection of T cells causing graft-versus-host disease across minor histocompatibility barriers: Role of the H-2 complex. J. Exp. Med. 151: 1114-1124, 1980.
Korngold R, Sprent J: Features of T cells causing H-2 restricted lethal graft-vs-host disease across minor histocompatibility barriers. J. Exp. Med. 155: 872-883, 1982.
Our major contribution in the 1980s was defining the biological roles of CD4 and CD8 T-cell subsets in causing GVHD. These observations helped serve as the basis for selective T-cell subset removal in clinical trials conducted at several institutions.
Korngold R, Sprent J: Lethal graft-versus-host disease following bone marrow transplantation across minor histocompatibility barriers in mice. Prevention by removing mature T cells from marrow. J. Exp. Med. 148: 1687-1698, 1978.
Korngold R, Sprent J: Selection of cytotoxic T-cell precursors specific for minor histocompatibility determinants. I. Negative selection across H-2 barriers induced with disrupted cells but not with glutaraldehyde-treated cells: Evidence for antigen-processing. J. Exp. Med. 151: 314-327, 1980.
Korngold R, Sprent J: Negative selection of T cells causing graft-versus-host disease across minor histocompatibility barriers: Role of the H-2 complex. J. Exp. Med. 151: 1114-1124, 1980.
Korngold R, Sprent J: Features of T cells causing H-2 restricted lethal graft-vs-host disease across minor histocompatibility barriers. J. Exp. Med. 155: 872-883, 1982.
T Cell Repertoire and GVHD/GVT separation
For the last seventeen years, we have been using T-cell repertoire analysis to define GVHD T-cell responses and those with GVT potential as a means of separating the effects to improve bone marrow transplantation (BMT) outcomes. Much of our early work in this arena utilized Vbeta CDR3 size spectratyping, which was on the cutting edge of the field at the time. More recently, we have been utilizing the newer techniques of next generation TCR sequencing, which is our current effort. In collaboration with my colleague Dr. Thea Friedman, we were able to dissect both CD4 and CD8 responses responsible for GVHD in the B6-> BALB.B model as well as others, and utilized spectratyping as a GVHD predictor of what would develop in BMT patients. Analysis of potential GVT responses in murine models also allowed us to manipulate selective donor T-cell populations in the graft to achieve GVT responses with minimization of GVHD.
Friedman TM, Gilbert M, Briggs C, Korngold R: Repertoire analysis of CD8+ T cell responses to minor histocompatibility antigens involved in graft-versus-host disease J. Immunol. 161:41-48, 1998.
Friedman TM, Statton D, Jones SC, Berger MA, Murphy GF, Korngold R: Vb repertoire analysis of CD4+ T cell responses to minor histocompatibility antigens involved in graft-versus-host disease. Biol. Blood Marrow Transplant. 7: 2-13, 2001.
Patterson AE, Korngold R: Infusion of select leukemia-reactive TCR Vb+ T cells provides graft-versus-leukemia responses with minimization of graft-versus-host disease following murine hematopoietic stem cell transplantation. Biol. Blood Marrow Transplant. 7: 187-196, 2001.
Jones SC, Friedman TM, Murphy GF, Korngold R: Specific donor Vb-associated CD4+ T cell responses correlate with severe acute graft-versus-host disease directed to multiple minor histocompatibility antigens. Biol. Blood Marrow Transplant. 10:91-105, 2004.
Fanning SL, Zilberberg J, Stein J, Vazzana K, Berger SA, Korngold R, Friedman TM: Unraveling graft-versus-host disease and graft-versus-leukemia responses using TCR Vβ spectratype analysis in a murine bone marrow transplantation model. J Immunol, 190:447-457, 2013.