Review Article| Volume 28, ISSUE 3, P469-479, September 2008

Download started.


Yin and Yan of Cytokine Regulation in Solid Organ Graft Rejection and Tolerance

      Solid organ transplantation is the therapy of choice for end stage diseases. The alloimmune response generated after transplantation induces the production of a “cytokine storm” that can lead to either the rejection of the organ or graft acceptance. These key decisions, which determine the transplant fate, depend on the type of cytokine response (Th1/Th2). An inflammatory response will lead to graft loss; a tolerogenic response assists in graft acceptance. A balance between different factors often determines outcome. The same cytokine may assist in either allograft rejection or graft survival depending on: (1) the cell types in the vicinity, (2) the amount of each cytokine produced, (3) different sites, and (4) if it acts in a synergistic or antagonistic manner with other cytokines. This review focuses on cytokines that manipulate the alloimmune response after organ transplantation and that play a role either in graft rejection (yin) or tolerance (yang).
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribers receive full online access to your subscription and archive of back issues up to and including 2002.

      Content published before 2002 is available via pay-per-view purchase only.


      Subscribe to Clinics in Laboratory Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Josien R.
        • Pannetier C.
        • Douillard P.
        • et al.
        Graft-infiltrating T helper cells, CD45RC phenotype, and Th1/Th2-related cytokines in donor-specific transfusion-induced tolerance in adult rats.
        Transplantation. 1995; 60: 1131-1139
        • Horak I.
        • Lohler J.
        • Ma A.
        • et al.
        Interleukin-2 deficient mice: a new model to study autoimmunity and self-tolerance.
        Immunol Rev. 1995; 148: 35-44
        • Refaeli Y.
        • Van Parijs L.
        • London C.A.
        • et al.
        Biochemical mechanisms of IL-2-regulated Fas-mediated T cell apoptosis.
        Immunity. 1998; 8: 615-623
        • Irmler M.
        • Thome M.
        • Hahne M.
        • et al.
        Inhibition of death receptor signals by cellular FLIP.
        Nature. 1997; 388: 190-195
        • Li X.
        The common gammac-cytokines and transplantation tolerance.
        Cell Mol Immunol. 2004; 1: 167-172
        • McLaughlin P.J.
        • Aikawa A.
        • Davies H.M.
        • et al.
        Evaluation of sequential plasma and urinary tumor necrosis factor alpha levels in renal allograft recipients.
        Transplantation. 1991; 51: 1225-1229
        • Heidenreich S.
        • Lang D.
        • Tepel M.
        • et al.
        Monocyte activation for enhanced tumour necrosis factor-alpha and interleukin 6 production during chronic renal allograft rejection.
        Transpl Immunol. 1994; 2: 35-40
        • Deng M.C.
        • Plenz G.
        • Labarrere C.
        • et al.
        The role of IL6 cytokines in acute cardiac allograft rejection.
        Transpl Immunol. 2002; 9: 115-120
        • Reinders M.E.
        • Sho M.
        • Izawa A.
        • et al.
        Proinflammatory functions of vascular endothelial growth factor in alloimmunity.
        J Clin Invest. 2003; 112: 1655-1665
        • Luscinskas F.W.
        • Cybulsky M.I.
        • Kiely J.M.
        • et al.
        Cytokine-activated human endothelial monolayers support enhanced neutrophil transmigration via a mechanism involving both endothelial-leukocyte adhesion molecule-1 and intercellular adhesion molecule-1.
        J Immunol. 1991; 146: 1617-1625
        • Bharat A.
        • Narayanan K.
        • Street T.
        • et al.
        Early posttransplant inflammation promotes the development of alloimmunity and chronic human lung allograft rejection.
        Transplantation. 2007; 83: 150-158
        • Tripp C.S.
        • Wolf S.F.
        • Unanue E.R.
        Interleukin 12 and tumor necrosis factor alpha are costimulators of interferon gamma production by natural killer cells in severe combined immunodeficiency mice with listeriosis, and interleukin 10 is a physiologic antagonist.
        Proc Natl Acad Sci U S A. 1993; 90: 3725-3779
        • Chang C.H.
        • Furue M.
        • Tamaki K.
        Selective regulation of ICAM-1 and major histocompatibility complex class I and II molecule expression on epidermal Langerhans cells by some of the cytokines released by keratinocytes and T cells.
        Eur J Immunol. 1994; 24: 2889-2895
        • Sandner S.E.
        • Clarkson M.R.
        • Salama A.
        • et al.
        Role of the programmed death-1 pathway in regulation of alloimmune responses in vivo.
        J Immunol. 2005; 174: 3408-3415
        • Yamada J.
        • Yoshida M.
        • Taylor A.W.
        • et al.
        Mice with Th2-biased immune systems accept orthotopic corneal allografts placed in “high risk” eyes.
        J Immunol. 1999; 162: 5247-5255
        • Niederkorn J.Y.
        Immune mechanisms of corneal allograft rejection.
        Curr Eye Res. 2007; 32: 1005-1006
        • Hargrave S.
        • Chu Y.
        • Mendelblatt D.
        • et al.
        Preliminary findings in corneal allograft rejection in patients with keratoconus.
        Am J Ophthalmol. 2003; 135: 452-460
        • Matzinger P.
        Friendly and dangerous signals: is the tissue in control?.
        Nat Immunol. 2007; 8: 11-13
        • Schwartz R.H.
        T cell anergy.
        Annu Rev Immunol. 2003; 21: 305-334
        • Schwartz R.H.
        Natural regulatory T cells and self-tolerance.
        Nat Immunol. 2005; 6: 327-330
        • Monk N.J.
        • Hargreaves R.E.
        • Simpson E.
        • et al.
        Transplant tolerance: models, concepts and facts.
        J Mol Med. 2006; 84: 295-304
        • Kingsley C.I.
        • Karim M.
        • Bushell R.
        • et al.
        CD25+ CD4+ regulatory T cells prevent graft rejection: CTLA-4- and IL-10-dependent immunoregulation of alloresponses.
        J Immunol. 2002; 168: 1080-1086
        • Onodera K.
        • Hancock W.W.
        • Graser E.
        • et al.
        Type 2 helper T cell-type cytokines and the development of “infectious” tolerance in rat cardiac allograft recipients.
        J Immunol. 1997; 158: 1572-1581
        • Wells A.D.
        • Li X.C.
        • Li Y.
        • et al.
        Requirement for T-cell apoptosis in the induction of peripheral transplantation tolerance.
        Nat Med. 1999; 5: 1303-1307
        • Dai Z.
        • Konieczny B.T.
        • Baddoura F.K.
        • et al.
        Impaired alloantigen-mediated T cell apoptosis and failure to induce long-term allograft survival in IL-2-deficient mice.
        J Immunol. 1998; 161: 1659-1663
        • Bushell A.
        • Niimi M.
        • Morris P.J.
        • et al.
        Evidence for immune regulation in the induction of transplantation tolerance: a conditional but limited role for IL-4.
        J Immunol. 1999; 162: 1359-1366
        • Li X.C.
        • Ima A.
        • Li Y.
        • et al.
        Blocking the common gamma-chain of cytokine receptors induces T cell apoptosis and long-term islet allograft survival.
        J Immunol. 2000; 164: 1193-1199
        • Lu L.F.
        • Lind E.F.
        • Gondek D.C.
        • et al.
        Mast cells are essential intermediaries in regulatory T-cell tolerance.
        Nature. 2006; 442: 997-1002
        • Kielar M.L.
        • John R.
        • Bennett M.
        • et al.
        Maladaptive role of IL-6 in ischemic acute renal failure.
        J Am Soc Nephrol. 2005; 16: 3315-3325
        • Yoshida S.
        • Haque A.
        • Mizobuchi T.
        • et al.
        Anti-type V collagen lymphocytes that express IL-17 and IL-23 induce rejection pathology in fresh and well-healed lung transplants.
        Am J Transplant. 2006; 6: 724-735
        • Chen Y.
        • Wood K.J.
        Interleukin-23 and TH17 cells in transplantation immunity: does 23+17 equal rejection?.
        Transplantation. 2007; 84: 1071-1074
        • Witowski J.
        • Ksiazek K.
        • Jorres A.
        Interleukin-17: a mediator of inflammatory responses.
        Cell Mol Life Sci. 2004; 61: 567-579
        • Li J.
        • Simeoni E.
        • Fleury S.
        • et al.
        Gene transfer of soluble interleukin-17 receptor prolongs cardiac allograft survival in a rat model.
        Eur J Cardiothorac Surg. 2006; 29: 779-783
        • Tang J.L.
        • Subbotin V.M.
        • Antonysamy M.A.
        • et al.
        Interleukin-17 antagonism inhibits acute but not chronic vascular rejection.
        Transplantation. 2001; 72: 348-350
        • Antonysamy M.A.
        • Fanslow W.C.
        • Fu F.
        • et al.
        Evidence for a role of IL-17 in organ allograft rejection: IL-17 promotes the functional differentiation of dendritic cell progenitors.
        J Immunol. 1999; 162: 577-584
        • Romagnani P.
        From basic science to clinical practice: use of cytokines and chemokines as therapeutic targets in renal diseases.
        J Nephrol. 2005; 18: 229-233
        • Moudgil A.
        • Puliyanda D.
        Induction therapy in pediatric renal transplant recipients: an overview.
        Paediatr Drugs. 2007; 9: 323-341
        • James D.G.
        A new immunosuppressant: tacrolimus.
        Postgrad Med J. 1996; 72: 586
        • Strehlau J.
        • Pavlakis M.
        • Lipman M.
        • et al.
        Quantitative detection of immune activation transcripts as a diagnostic tool in kidney transplantation.
        Proc Natl Acad Sci U S A. 1997; 94: 695-700
        • Li X.C.
        • Roy-Chaudhury P.
        • Hancock W.W.
        • et al.
        IL-2 and IL-4 double knockout mice reject islet allografts: a role for novel T cell growth factors in allograft rejection.
        J Immunol. 1998; 161: 890-896
        • Ruchatz H.
        • Leung B.P.
        • Wei X.Q.
        • et al.
        Soluble IL-15 receptor alpha-chain administration prevents murine collagen-induced arthritis: a role for IL-15 in development of antigen-induced immunopathology.
        J Immunol. 1998; 160: 5654-5660
        • Lewis E.
        • Weiler M.
        • Chaimovitz C.
        • et al.
        Interleukin-15 is the main mediator of lymphocyte proliferation in cultures mixed with human kidney tubular epithelial cells.
        Transplantation. 2001; 72: 886-890
        • Ku C.C.
        • Murakami M.
        • Sakamoto A.
        • et al.
        Control of homeostasis of CD8+ memory T cells by opposing cytokines.
        Science. 2000; 288: 675-678
        • Tellides G.
        • Pober J.S.
        Interferon-gamma axis in graft arteriosclerosis.
        Circ Res. 2007; 100: 622-632
        • Duncan M.D.
        • Wilkes D.S.
        Transplant-related immunosuppression: a review of immunosuppression and pulmonary infections.
        Proc Am Thorac Soc. 2005; 2: 449-455
        • O'Shea J.J.
        • Park H.
        • Pesu M.
        • et al.
        New strategies for immunosuppression: interfering with cytokines by targeting the Jak/Stat pathway.
        Curr Opin Rheumatol. 2005; 17: 305-311
        • Changelian P.S.
        • Flanagan M.E.
        • Ball D.J.
        • et al.
        Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor.
        Science. 2003; 302: 875-878