**3.2 Acute rejection**

Acute rejection can occur within 24 hours of graft implantation and continue over a period of days to weeks. Acute rejection commonly manifests within the first 6 months after transplantation.

Acute cellular rejection is mediated by lymphocytes that have been activated against donor antigens, primarily in the lymphoid tissues of the recipient. Graft antigens are recognized by T cells and the resulting release of cytokines eventually leads to tissue distortion, vascular insufficiency, and cell destruction. Histologically, leukocytic infiltration that is dominated by equivalent numbers of macrophages and T cells is observed within the interstitium. The donor dendritic cells, which are also called passenger leukocytes, enter the circulation and function as antigen-presenting cells (APCs).

The primary aim of immunosuppression has been to control acute rejection by allowing time for tissue repair to occur. Most combination therapies block T-cell activation by providing intense immunosuppression during the immediate post-transplantation period known as the induction phase. Later, during the immunosuppressive maintenance phase, multiple-drug cocktails are administered to maintain a state of low- or nonresponsiveness to the allograft.

#### **3.3 Chronic rejection**

Chronic rejection develops months to years after acute rejection episodes have subsided. Chronic rejections are both antibody- and cell-mediated. The use of immunosuppressive drugs and tissue-typing methods has increased the survival of allografts in the first year, but chronic rejection remains unpreventable in most cases[5].

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, and organ reperfusion injury.

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 has been proposed to improve long-term outcomes.
