**3. Role of T cells**

The introduction of an "allograft" into an immunocompetent individual would typically result in a process of recognizing the graft tissue as foreign "allorecognition" and the initiation of what is known as an "alloresponse", invariably resulting in tissue inflammation, architectural distortion and infiltration by T-cells that are responsive to the graft resulting in loss of function and eventual failure of the graft, a process we call acute cellular rejection. This occurs after a number of steps taking place at the molecular and cellular level, steps that have been recognized and become the target of therapy in order to prevent rejection.

Allorecognition can occur by three well-described mechanisms referred to as direct, indirect and the semi direct pathways. (Safinia et al, 2010). In the direct pathway recipient T cells recognize intact allogeneic major histocompatibility complex or MHC-peptide complexes expressed by foreign cells, while in the indirect pathway T cells recognize peptides derived from allogeneic MHC proteins presented by antigen-presenting cell and finally the semi

The Allo-Immunological Injury in Chronic Allograft Nephropathy 405

T-cell subtype. The indirect alloresponse, while less rapid compared with the direct pathway, dominates reactivity to transplanted antigens in the long term. This is the main reason why, despite tolerance afforded by the direct pathway, immune suppression is required for as long as the graft remains viable. Any inflammation induces the expression of MHC class II molecules on endothelial and epithelial cells in the graft, conferring the ability

Clinically, the activity of T-cells in renal allografts is represented by cellular rejection. The diagnosis is made by detecting tubulitis, interstitial infiltration and edema, and sometimes intimal arteritis. A grade is assigned depending on the severity of these lesions. The inflammatory activity of T-cells results in renal injury resulting in architectural distortion of the renal parenchyma. The Banff Classification for T-cell mediated rejection along with

iii. Transmural arteritis and/or arterial fibrinoid change and necrosis of medial smooth

'Chronic allograft arteriopathy' (arterial intimal fibrosis with mononuclear cell

Fig. 2. Infiltration of tubules and interstitium with T cells (*Courtesy of Suzanne Meleg-Smith,* 

Based on the principles of immunology, B cells are known to play vital roles, from antigen presentation, immune regulation, to their most characteristic role of differentiating into plasma cells that secrete antibodies. The secretion of antibodies and their role in the pathogenesis of CAN is what makes B cells of great clinical significance in the long term

histological description of each category and sub category is described below.

muscle cells with accompanying lymphocytic inflammation (Figure 4)

to present antigen to CD4+ T cells (Bal et al., 1990).

Acute T-cell mediated rejection (Type/Grade)

ii. Intimal arteritis (vascular rejection) (Figure 3)

i. Significant tubular and interstitial infiltration (Figure 2)

infiltration in fibrosis, formation of neo-intima)

**3.1 T-cell mediated rejection** 

Chronic T-cell mediated rejection

**4. Role of B cells and DSA** 

survival of the renal graft.

*MD.*)

direct pathway where recipient dendritic cells acquire intact allogeneic MHC–peptide complexes from donor cells and present them to recipient T cells. (Harrera et al., 2004; Lechlar and Batchelar, 1982; Warrens et al., 1994). In the context of transplantation, while the direct and the indirect pathways are well recognized and understood, the semi-direct pathway is not known to be of clinical importance in allograft rejection. (Figure 1)

Fig. 1. Mechanism of antigen presentation in the direct and indirect pathways.

As far as the direct pathway is concerned, if the immunological milieu is left unaltered, a strong and effective alloresponse would follow primarily due to the very high number of recipient T-cells that will recognize the transplant tissue as foreign. Due to the nature of this mechanism, this pathway is of primary importance in the immediate post transplant period. T-cell depletion using various immunosuppressive regimens, including induction protocols, severely compromises this process. Another phenomenon observed is depletion of donor derived dendritic cells through apoptosis and elimination by recipient immune reactivity. This is also accompanied by a decline in the number of recipient T cells with direct antidonor allospecificity with time, most pronounced in the CD4+ CD45RO+ (memory) subset (Hornick et al, 1998). However, this decline in direct pathway responses with time is as pronounced in patients with chronic rejection as in those with stable graft function and this supports the view that the direct pathway of allorecognition is of little importance in the context of chronic graft failure.

As the direct pathway declines with time, recipient dendritic and other antigen presenting cells travel through the graft, picking up soluble MHC alloantigens or antigens derived from donor cells and present them to T-cells activating CD4 + and CD 8+ cells (the indirect pathway) (Auchincloss et al. , 1993; Kievits et al.,1991). The predominant antigen presentation is done through MHC-Class II cells which have an affinity towards the CD4+ T-cell subtype. The indirect alloresponse, while less rapid compared with the direct pathway, dominates reactivity to transplanted antigens in the long term. This is the main reason why, despite tolerance afforded by the direct pathway, immune suppression is required for as long as the graft remains viable. Any inflammation induces the expression of MHC class II molecules on endothelial and epithelial cells in the graft, conferring the ability to present antigen to CD4+ T cells (Bal et al., 1990).

Clinically, the activity of T-cells in renal allografts is represented by cellular rejection. The diagnosis is made by detecting tubulitis, interstitial infiltration and edema, and sometimes intimal arteritis. A grade is assigned depending on the severity of these lesions. The inflammatory activity of T-cells results in renal injury resulting in architectural distortion of the renal parenchyma. The Banff Classification for T-cell mediated rejection along with histological description of each category and sub category is described below.
