**2. The alloimmune response**

The allogeneic immune response has largely been attributed to the recognition of donor antigens, presented in the context of human leukocyte antigen (HLA) molecules to T cells,

which in turn direct a huge array of cellular and humoral responses, causing tissular damage and graft rejection. This type of response is mediated by the adaptative branch of the immune system [7].

allogeneic or donor cells is extraordinarily high compared with the number of clones that target

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**Figure 1.** The alloimmune response: (A) ischemia may initiate an innate immune response, (B) which contributes to acute and chronic allograft rejection. The initial allograft injury, during reperfusion, is associated with generation of DAMPs for maturation of donor-derived and recipient-derived dendritic cells, (C) which represents the bridge to the development of an adaptive alloimmune response that results in rejection. Abbreviations: DAMPs, Damage-Associat‐

In the indirect pathway, T cells recognize processed alloantigen presented as peptides by self-APCs (host-APCs) [11]. The basic premise for indirect allorecognition as a mechanism involved in allograft rejection is shedding of donor HLA molecules from the graft. These HLA molecules are then taken up by recipient APCs and presented to CD4+ T cells. Interestingly, there is also evidence that demonstrates that recipient DCs can acquire and process intact donor HLA molecules from donor cell debris and stimulate CD8+ T cells by cross priming. Therefore, both CD4+ and CD8+ T cells mediate indirect allorecognition [11]. The indirect pathway is postu‐

ed Molecular Patterns; NF- κβ, Nuclear Factor- κappa beta; DC, Dendritic Cell.

lated to play a dominant role in chronic allograft rejection [15].

**2.2. Indirect allorecognition pathway**

antigen presented by self-APCs [14].

The immune system can be divided in two components, the innate and adaptative immunity. The innate immunity, refers to a nonspecific response that involves the recruitment of diverse components of the immune system such as, macrophages, neutrophils, natural killer cells (NK cells), cytokines, several cellular receptors, complement components, cytokines, Toll-like receptors (TLRs), and antimicrobial peptides (AMP's). The adaptative immunity, which involves recognition of specific antigen, conferring both specificity and a memory effect [8]. Data suggest that initial allograft injury (such as ischemia) may initiate an innate immune response (Figure 1A), thus contributing to acute and chronic allograft rejection. Furthermore, this inflammatory response may initiate and expand the adaptive immune response to the point where the different HLA antigens come into play for the first time [9]. Some immunol‐ ogist choose not to divide the alloimmune response in adaptative and innate branches; nevertheless, they are closely related and dependent on each other.

The main and strongest responses to alloantigens are mediated by host T cells, which recognize peptide antigens presented by antigen presenting cells (APCs) in the context of HLA. The phenomenon by which the recipient immune system reacts with donor antigens that are considered to be "non-self" is called allorecognition. Foreign or donor antigen presentation to T cells may occur by either direct or indirect pathways [10] (Figure 2A).

#### **2.1. Direct allorecogniton pathway**

The direct allorecognition pathway involves recognition of intact donor HLA molecules on the donor cells, usually APCs. This seems to contradict the classic self-HLA restriction property of T cells, since the peptide being recognized is presented in a non-self HLA, and to date, two models have been proposed to explain this discrepancy [11].

The "high determinant density" model proposes that the transplanted organ carries a variable number of passenger APCs in the form of interstitial dendritic cells (DCs). Such APCs have a high density of allo-HLA molecules and are capable of directly stimulating the recipient's T cells. Given the very high ligand density, the affinity of alloreactive T cell receptors required to generate an optimal alloimmune response can be significantly lower compared to that required for self-HLA peptide complex [12].

In the "multiple binary complex" model, peptides derived from endogenous proteins that are bound into the groove of donor HLA molecules play a role. These peptides are derived from the same normal cellular proteins that are present even in the recipient. However, the differ‐ ences in the allo-HLA groove causes a different set of peptides to be presented from homolo‐ gous proteins. These peptides can be recognized by the recipient T cells. Therefore, even a single HLA mismatch between the donor and the recipient would be able to stimulate a large number of alloreactive T cells [13].

This pathway is thought to be the dominant pathway involved in the early alloimmune response (acute graft rejection), as the relative number of T cells that proliferate on contact with allogeneic or donor cells is extraordinarily high compared with the number of clones that target antigen presented by self-APCs [14].

**Figure 1.** The alloimmune response: (A) ischemia may initiate an innate immune response, (B) which contributes to acute and chronic allograft rejection. The initial allograft injury, during reperfusion, is associated with generation of DAMPs for maturation of donor-derived and recipient-derived dendritic cells, (C) which represents the bridge to the development of an adaptive alloimmune response that results in rejection. Abbreviations: DAMPs, Damage-Associat‐ ed Molecular Patterns; NF- κβ, Nuclear Factor- κappa beta; DC, Dendritic Cell.
