**2.2. Indirect allorecognition pathway**

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

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;

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

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

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

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

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

nevertheless, they are closely related and dependent on each other.

T cells may occur by either direct or indirect pathways [10] (Figure 2A).

models have been proposed to explain this discrepancy [11].

**2.1. Direct allorecogniton pathway**

464 Current Issues and Future Direction in Kidney Transplantation

required for self-HLA peptide complex [12].

number of alloreactive T cells [13].

system [7].

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

receptors) that recognize classical HLA class I molecules [19] and CD94/NKG2 receptors that recognize non-classical HLA class I molecules. Currently, the role of NK cell-mediated cytotoxicity in allograft rejection remains controversial, but recent data shows that NK cells are potent alloreactive cells when fully activated with IL-15 and can mediate potent acute skin rejection, at least in a murine model [20]. While reports continue to provide evidence support‐ ing a role for NK cells in promoting rejection, there are a growing number of studies that illustrate an alternative role for NK cells in promoting allograft survival and tolerance [21].

Through their specific antigen receptors, T cells are capable of recognizing external antigens and initiating immune responses. These reactions may be characterized predominantly by cellmediated reactions in which effector immune cells play a major role; or by humoral reactions in which the stimulation of B cells (Figure 2D) may induce antibody responses. The T cells orchestrate both the initiation and the propagation of immune responses, largely through the secretion of protein mediators termed cytokines and chemokines. Moreover, recent findings suggest that a novel subtype of T cells, named regulatory T cells, have an important role in achieving allograft tolerance [22]. These facts make T cells important targets for immunosup‐

T cells require two separate signals before activation occurs. The first signal is antigen specific and is provided by the interaction of a T cell receptor (TCR) with a peptide antigen presented within the antigen binding groove of HLA molecules on the surface of APCs (Figure 2A). These are HLA class I molecules in the case of CD8+ T cells and class II molecules in the case of CD4+ T cells. The second, costimulatory, signal is provided by the interaction of T cell surface

CD154 interactions. The first signal in the absence of the second signal may lead to T cell inactivation, anergy, or failure of a Th1 (T helper cell-1) response with a switch to a Th2 (T

The Th1/Th2 response refers to the pattern of cytokines produced by T helper cells. Th1 cells produce interleukin-12 (IL-12) and interferon gamma (IFN-gamma) inducing macrophage activation leading to delayed-type hypersensitivity responses. The Th1 response has been implicated in acute allograft rejection. Th2 cells produce IL-4, IL-5, IL-10, and IL-13, and provide help for B cell function [24]. IL-4 is a growth factor for B cells and antibody production, and also can directly inhibit T cell maturation along the Th1 pathway [25]. Such responses have been associated with allograft tolerance, but are mainly implicated in clearing parasitic

Once the binding of CD4/CD8 co-receptors stabilizes the immunologic synapse between the T cell and the APC, tyrosine-based activation motifs on the CD3 complex leads to the phos‐ phorylation of a series of intracellular proteins, resulting in the activation of a variety of enzymes including calcineurin, and the activation of transcription factors, such as nuclear factor of activated T cells (NFAT) and NF-κβ, permitting the transcription of different genes,


Tolerance in Renal Transplantation http://dx.doi.org/10.5772/54734 467

molecules with their ligands on APCs, being the most important the B71

**2.4. Activation of T cells**

helper cell-2) response [23].

1 B7-1 (or CD80) and B7-2 (or CD86).

presive therapy and tolerance induction protocols.

infections and the presentation of allergic diseases.

**Figure 2.** A). Allorecognition process. Two pathways lead to T-cell activation, the direct pathway and the indirect pathway. The mechanisms of tolerance are: (B) Central tolerance in which T cells migrate from the bone marrow to the thymus where they are educated, such that those recognizing self-antigens are deleted, and (C) Peripheral mecha‐ nisms of tolerance for self-reactive T cells including AICD, anergy, and suppression by Treg. (D) B-cell awaiting the prop‐ er stimulus of a T-cell to initiate the production of alloantibodies. Two possible scenarios ensure tolerance: deletion of these self-reactive B cells and receptor editing, which is a process by which a new receptor with altered specificity is generated through another sequence of B cell receptor gene rearrangements. Abbreviations: HLA, Human Leukocyte Antigen; APC, Antigen Presenting Cells; TCR, T-cell Receptor; T, T-cell; T reg, regulatory T cells; B, B-cell; IL-2; Interleu‐ kin-2; AICD, Activation-Induced Cell Death.

#### **2.3. Other allorecognition pathways**

A third mode of allorecognition, which Lechler's group has termed the "semi-direct" pathway, has been recently proposed [16]. This model is based on the transfer of intact HLA molecules between cells. DCs have been shown to acquire intact HLA class I and II molecules from exosomes secreted by other DCs and to prime both naïve CD8+ and CD4+ T cells, thereby inducing an alloimmune response [17,18].

Another mechanism of allorecognition involves NK cells. NK cells may recognize HLA classical and non-classical type I molecules through interactions with cell surface receptors called killer cell immunoglobulin-like receptors (KIR, formerly named killer inhibitory receptors) that recognize classical HLA class I molecules [19] and CD94/NKG2 receptors that recognize non-classical HLA class I molecules. Currently, the role of NK cell-mediated cytotoxicity in allograft rejection remains controversial, but recent data shows that NK cells are potent alloreactive cells when fully activated with IL-15 and can mediate potent acute skin rejection, at least in a murine model [20]. While reports continue to provide evidence support‐ ing a role for NK cells in promoting rejection, there are a growing number of studies that illustrate an alternative role for NK cells in promoting allograft survival and tolerance [21].
