**4.2 T cell-mediated rejection**

Although other cell types are also involved, T cells are central in graft rejection. The rejection reaction consists of the sensitization stage and the effector stage.

#### *Sensitization stage*

98 Liver Transplantation – Basic Issues

Although chronic rejection appears as fibrosis and scarring in all transplanted organs, the specific histopathological picture depends on the organ transplanted. In liver transplants, chronic rejection is characterized by vanishing bile duct syndrome. Histologically, progressive neointimal formation occurs within large and medium arteries and, to a lesser extent, within the veins of the graft. Leukocyte infiltration usually is mild or absent. These processes result in reduced blood flow, with subsequent regional tissue ischemia, fibrosis, and cell death. In chronic rejection, pathologic tissue remodeling results from peritransplant and posttransplant trauma. Cytokines and tissue growth factors induce smooth muscle cells to proliferate, migrate, and produce new matrix material. Interstitial fibroblasts are also induced to produce collagen. The factors that can increase the risk of chronic rejection include previous episodes of acute rejection, inadequate immunosuppression, extended periods of cold ischemia, the development of posttransplant infections such as cytomegalovirus (CMV), initial delayed graft function,

Currently, unless inadequate immunosuppression is the cause of rejection, no accepted therapeutic strategies exist for the reversal of chronic rejection. The CD40 and CD28 pathways have been proposed as being important in initiating T-cell responses and lowering T-cell activation thresholds, respectively. Therefore, blocking T-cell costimulation

The immune response to a transplanted organ consists of both cellular (lymphocytemediated) and humoral (antibody-mediated) mechanisms. The evolving understanding of

Humoral rejection is a form of allograft injury and subsequent dysfunction that is primarily mediated by antibodies and complement. The antibodies involved are either preformed antibodies or anti-donor antibodies that develop following transplantation. Proteinuria is associated with donor-specific antibody detection; it is likely an important factor in the rapid decline in glomerular filtration rates and early graft failure in patients that develop de novo anti-HLA antibodies. The presence of even low levels of donor-specific antibodies, which may not be detected by complement-dependent cytotoxic and flow cytometry crossmatches, have been shown to be associated with inferior allograft outcomes. These

Following transplantation, the inactive product C4d from the classical complement activation pathway is deposited in peritubular capillaries (PTC); immune detection of this product in allograft biopsies is used for the diagnosis of antibody-mediated rejection. However, one study reported substantial fluctuations in C4d Banff scores in the first year following transplantation[8]; these authors suggested that these results may reflect the dynamic and unpredictable nature of the humoral process. Thus, C4d by itself may not be a sufficiently sensitive indicator, and detection of microvascular inflammation utilizing donor-specific antibodies may be more useful for diagnosing antibody-mediated

and organ reperfusion injury.

**4. Mechanisms of rejection** 

**4.1 Acute humoral rejection** 

rejection.

has been proposed to improve long-term outcomes.

liver allograft rejection was reviewed by Eksteen[23].

patients may require augmented immunosuppression.

In this stage, CD4 and CD8 T cells, via their T-cell receptors, recognize the alloantigens expressed on the cells of the foreign graft. Two signals are needed for antigen recognition; the first is provided by the interaction of the T cell receptor with the antigen presented by an MHC molecule, while the second signal is provided by a costimulatory receptor/ligand interaction. Of the numerous costimulatory pathways, the interaction of CD28 on the T cell surface with its APC surface ligands, B7-1 or B7-2 (commonly known as CD80 or CD86, respectively), has been most studied. In addition, cytotoxic T lymphocyte–associated antigen-4 (CTLA4) on T cells also binds to these ligands, providing an inhibitory signal. Other costimulatory molecules include CD40 and its ligand, CD40L (CD154)[9, 10].

Typically, the helices of the MHC molecules form the peptide-binding groove and are occupied by peptides derived from normal cellular proteins. Thymic or central tolerance mechanisms (clonal deletion) and peripheral tolerance mechanisms, such as anergy, ensure that these self-peptide MHC complexes are not recognized by T cells, thereby preventing autoimmune responses.

At least 2 distinct, but not necessarily mutually exclusive, pathways of allorecognition exist: the direct and indirect pathways. Each leads to the generation of different sets of allospecific T cell clones.
