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Kristine S. Schonder • Robert J. Weber • John J. Fung • Thomas E.Starzl ----------------------------------------------------------------------- Advances in molecular biology and immunology have pro POINTS vided for greater understanding of the mechanisms involved in allograft rejection. Many of the key pathways of organ . "1. Allograft rejection is mediated primarily by the rejection are targeted by the growing armamentarium of T cell in response to the presence of an antigen, which immunosuppressive drugs available today. The vast array of is processed by antigen-presenting cells (APC) and immunosuppressive combinations has dramatically decreased carried on the major histocompatibility complex the incidence of acute allograft rejection. However, very little (MHC) molecules to the T cell. ground has been gained with respect to the impact of chronic allograft rejection on long-term allograft survival. The T-cell receptor (TCR), in conjunction with Furthermore, the relative nonselectivity of the current accessory molecules such as CD3, CD4, and CD8, immunosuppressants with long-term use can lead to the interacts with the antigen fragment on the development of malignancies and opportunistic infections. MHC molecule and produces the growth factor As we continue to explore different combinations of interleukin-2 (IL-2) to activate the T cell and immunosuppressants and new immunosuppressive pathways, stimulate proliferation of the T cell. we will continue to grow in our comprehension of the During allograft rejection, cytokines attract various immune system and come closer to true allograft acceptance. cells into rejecting allografts, stimulate the produc tion of antibodies, and produce inflammation. Effective immunosuppressive protocols combine BASIC PRINCIPLES OF multiple drugs targeted at different sites of the IMMUNOSUPPRESSION T-cell activation cascade. Corticosteroids block the early steps of T-cell Optimal immunosuppression, as it relates to transplantation, activation; they are used in tapering doses during is defined as the level of drug therapy that achieves graft the induction and maintenance phases of immuno acceptance with least suppression of systemic immunity. suppressive protocols and in high, brief doses for By optimizing immunosuppressive therapy, systemic toxicity the reversal of acute rejection episodes. (i.e., infection and malignancy) and other side effects can be minimized, albeit not entirely eliminated. Because monitoring The backbone of immunosuppressive protocols of blood levels and titration of immunosuppression on this are the calcineurin inhibitors cyclosporine and basis is possible with only a few agents, in practice, oversup tacrolimus, which inhibit IL-2 production and pression or undersuppression almost invariably becomes T-cell activation and proliferation. apparent only in retrospect. Recently, monitoring of CD3+ Azathioprine and mycophenolate mofetil inhibit cell counts has provided an alternative means of measuring synthesis, thereby disrupting the cell cycle the degree of immunosuppression. T-cell proliferation. Current immunosuppression protocols typically use S'Iro lim us blocks the cellular response to IL-2 and multiple drugs, each directed at a discrete site in the T-cell the progression of the cell cycle, inhibiting activation cascade.! Most immunosuppressive regimens proliferation. combine drugs, often with differing modes of action and tox globulin and monoclonal icities, allowing lower doses of each drug. Transplantation are potent cytotoxic compounds that immunosuppression can be (1) pharmacologic, consisting of rapid, profound, and prolonged T-cell deple drugs such as corticosteroids, cytokine suppressive agents, and .they are effectively used to reverse acute cell cycle inhibitors, or (2) biologic, consisting of monoclonal episodes or as induction therapy before and polyclonal antilymphocyte antibodies and anticytokine '''l~;nl'n+°tion. receptor antibodies.2 The combination of cyclosporine or tacrolimus with a ~oncentration monitoring is necessary to corticosteroid forms the backbone of most maintenance . efficacy in preventing allograft rejection immunosuppressive regimens being used today. An anti mlDimizing the potential for significant proliferative agent may also be added. In general, the early ~ffects; monitoring aids in the management postoperative period calls for the greatest degree of Interactions, particularly with cyclosporine, immunosuppression. As time goes on, many patients can and sirolimus therapy. maintain graft function with smaller doses of immuno suppressive agents. :c""0 If acute cellular rejection occurs, it is common to treat The MHC molecule carries the peptide fragment t » with a brief course of high-dose corticosteroid therapy, anti surface, where it is displayed to T cells in the host a :Xls: » lymphocyte antibodies, or both. Generally, high doses of a organs. Thus, there are three essential requirements 8 corticosteroid are used initially to reverse the acute attack on adaptive immune response known as rejection: (1) th g the allograft. Antilymphocyte antibody therapy with mono ence of an antigen fragment or protein (a ligand) at.~ -< surface of the APC, (2) a receptor fit for the liga de » clonal or polyclonal antibodies is used for more severe z (3) the activation of T cells. n , and o rejection or if corticosteroid therapy fails. Induction therapy, also called prophylactic therapy, refers The migration pattern of the antigen also is a .. ~ to the use of antilymphocyte antibodies immediately after factor. The only mobile antigen in organ transpla c~~ca] 8 consists of passenger leukocytes of bone marrow ori: :n 5 transplantation. This practice is based on the theory that G1 early incapacitation of the immune system may reduce the are present in the graft and that migrate prompt:; t -< likelihood of subsequent rejection. Claimed benefits are preferentially to host lymphoid organs.9- 11 These orga and . d h . 1 h·d 11 . ns or delayed onset of acute rejection, fewer episodes of rejection, or~anlZe .eterotoplC ymp 01 co ectlOns . provide the and no significant increase in infectious complications.3,4 umque archItectural structure and cellular mIlieu whe . The related concept of sequential therapy was introduced in factors that are necessary for progression from an imm:~~ response to the significant renal toxicity of cyclosporine genic environment to a tolerogenic environment are preseot observed in recipients of liver, heart, and kidney transplants. in abundance. These factors include cytokines, other mOln. The practice is to use antibody therapy for the first 1 to 2 weeks cuIes, cell-cell proximity, and homing mechanisms th:t after transplantation-the period in which renal injury is ensure an efficient response to the antigen. 12 In the lymphoid most likely to occur from a variety of insults. Cyclosporine organs, dendritic cells and other APCs that have captured therapy is not used during this period but is started later. and processed the antigen present the peptide fragment of The impact of this strategy on long-term renal function is the antigen to antigen-specific TCRs in the context of their c, much less clear. upregulated host MHC peptide. j:'C This early intensification of immunosuppression is not The efferent (effector) phase begins with the secretion 0(;" universally accepted. Some experts voice concern because of interleukin-2 (IL-2, or T-cell growth factor) and interferon.a . the well-known association between antilymphocyte antibody (IFN -a) by activated lymphocytes. The antigen-specific therapy (and immunosuppression in general) and infection immune activation and clonal expansion is aborted unless and malignancy.5,6 Others describe no benefit, greater there is upregulation by the APCs of "accessory" cell-bound Me expense,? or the successful use of regimens that avoid induc (costimulatory) molecules that sustain accelerated production and t tion altogether.8 Intermediate strategies involve the use of of IL-2 and foster the secretion of numerous other cytokines IL-2R induction only in high-risk patients or the use of just one dose (e.g., IL-l, IL-6, IL-9, IL-I0, IFNs, tumor necrosis factor-a advar of an antilymphocyte agent, followed by early evaluation of [TNF-aJ, TNF-P) and growth factors (granulocyte colony· of the renal function. stimulating factor [G-CSF] and granulocyte-macrophage guide, Although some patients can tolerate complete withdrawal colony-stimulating factor [GM-CSF])P The sequential nature site-d of immunosuppressive therapy without exhibiting rejection,3 of the response amplification has been obscured by use of step c it is best done as a protocol-based strategy with patients the term "costimulatory" to describe the accessory molecules, drugs under strict supervision. The current general approach is to implying that the afferent and early effector phases are minimize long-term immunosuppression. Various withdrawal simultaneous. SPEC protocols target individual components of the immunosup The TCR is a cell surface molecule that associates with pressive regimen (e.g., corticosteroids, calcineurin inhibitors) "accessory" molecules, including CD3, and either CD4.or CORl in an attempt to decrease serious complications of immuno CDS. The TCR-CD3 complex interacts with the peptl~e suppression; namely, infection, malignancy, and renal fragment carried by the MHC molecule of the APe. This Corti, dysfunction. complex is stabilized by the CD4 or CDS molecul~ ~~ the . doses, T cell. This interaction produces the signal

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