**2. Activation of innate immunity in kidney transplantation**

Innate immune responses are required for the activation of cellular and molecular mechanisms behind the physiopathology of kidney transplantation [4]. During the early stages of transplantation, innate immunity is essential for the activation of the adaptive immune system, whereas at later stages, innate components promote an inflammatory microenvironment that enhances allograft damage.

#### **2.1. Cells of the innate immune system**

The cellular components of innate immunity are phagocytic leukocytes (neutrophils, monocytes, eosinophils, and basophils), natural killer (NK) cells, and dendritic cells (DCs). Ischemic injury that occurs during organ transplantation promotes alloimmune responses including innate cell recruitment [5]. Infiltrating neutrophils release proteases, free radicals, and proinflammatory molecules such as interleukin 6 (IL-6), interleukin 8 (IL-8), and tumor necrosis factor alpha (TNF-α) within the graft. It has been demonstrated that a high neutrophil-lymphocyte ratio amplifies the inflammatory process during acute renal failure [6]. Furthermore, neutrophil-depleted mice and intracellular adhesion molecule 1 (ICAM-1) knockouts are more resistant to renal ischemic injury; suggesting that neutralizing neutrophil activity could increase transplant success rates by reducing early graft damage [7]. Macrophages are also an important source of interleukin 1 (IL-1), IL-6, transforming growth factor beta (TFG-*β*), interferon *γ*-induced protein 10 (IP-10), monocyte chemoattractant protein 1 (MCP-1), and macrophage inflammatory protein 2 (MIP-2) during ischemia [8]. In the context of renal damage, monocytes are recruited within the first few days thanks to C–C chemokine receptor type 2 (CCR2) and CX3C chemokine receptor 1 (CX3CR1) ligand release. Subsequently, these monocytes are transformed into macrophages able to phagocyte damaged cells and present peptides to alloreactive T cells in peripheral lymph nodes [8, 9]. There is NK cell recruitment after ischemia and during the early stages of renal transplantation [10, 11]. NK cells keep other cells in check for major histocompatibility complex (MHC) surface expression through killer Ig-like receptors (KIR) [12]. In allotransplantation, lack of MHC Class I recognition triggers NK effector mechanisms, including perforin-dependent cell lysis and cytokine production [13]. NK cells seem to play an important role in the induction of acute renal damage and long-term graft survival as demonstrated in mice that exhibit abnormalities in recruitment of these cells and are more resistant to kidney damage [10, 11].

#### **2.2. Role of pattern recognition receptors and damaging molecular patterns in renal transplantation**

In the early 1990s, Janeway proposed that all innate immune cells had pattern recognition receptors (PRRs) that can discriminate between self-components and pathogens. Soon after, Polly Matzinger suggested that our immune system is designed to recognize signs of harm rather than to discriminate between self and nonself, which could explain how innate immune activation can occur under sterile conditions such as in allotransplantation [14]. Consequently, pathogen-associated molecular patterns (PAMPs) and DAMPs are designed to signal damage threats [15]. DAMPs and PAMPs arise in the allograft during pre- and posttransplant periods; and activation of vascular PRRs such as TLRs, C-type lectin receptors, Nod-like receptors, and retinoic acid-inducible gene-I-like receptors can trigger production of proinflammatory cytokines [4].

The surgical process as well as ischemic injury, precondition for a systemic inflammatory reaction by releasing high mobility group box 1 (HMGB1) and heat shock proteins; as well as by increasing Toll-like receptor 4 (TLR4) expression in endothelial and peripheral blood cells [16]. The immunosuppressant cyclosporin A also induces HMGB1 release and promotes immune cell infiltration into the renal graft [17]. Furthermore, blocking HMGB1 reduced cellular infiltrate, IL-6 and TNF-*α* production in kidneys subjected to ischemia, and decreased of MCP-1 which is reflected in reduced nephrotoxicity [18]. On the other hand, HMGB1 appears to play a protective role; the administration of recombinant HMGB1 prevents dysfunction, tissue damage, and inflammation in animals subjected to ischemia [19].

#### **2.3. The complement system**

(OPTN), there are currently close to 100,000 people in the U.S. waiting for a lifesaving kidney transplant. Only between January and May 2017, 14,075 kidney transplants took place in the United States; of which 11,702 organs came from deceased donors and 2373 came from living donors. Renal transplantation has become the treatment of choice for patients with end-stage renal disease (ESRD); though its success and widespread use are still limited by the availability of suitable organs and allograft rejection [1]. In recent decades, shortterm graft survival has improved significantly as consequence of better donor matching systems, novel immunosuppressive agents and enhanced care. Unfortunately, long-term outcomes remain unfavorable and reflect subclinical injury caused by antibody-mediated allograft rejection (ABMR) [2]. The immune system lies at the intersection between immunogenic tolerance and graft failure and as such, it is a major determinant of pathology in the context of renal transplantation [3]. The immune system is a complex network of lymphoid organs, cells, and molecules responsible for body homeostasis and host defense. Although the main function of the immune system is to protect against external pathogens and molecules, the presence of foreign antigens on the donor organ also triggers innate and adaptive immune responses in the recipient that will largely determine graft performance

**2. Activation of innate immunity in kidney transplantation**

Innate immune responses are required for the activation of cellular and molecular mechanisms behind the physiopathology of kidney transplantation [4]. During the early stages of transplantation, innate immunity is essential for the activation of the adaptive immune system, whereas at later stages, innate components promote an inflammatory microenvironment

The cellular components of innate immunity are phagocytic leukocytes (neutrophils, monocytes, eosinophils, and basophils), natural killer (NK) cells, and dendritic cells (DCs). Ischemic injury that occurs during organ transplantation promotes alloimmune responses including innate cell recruitment [5]. Infiltrating neutrophils release proteases, free radicals, and proinflammatory molecules such as interleukin 6 (IL-6), interleukin 8 (IL-8), and tumor necrosis factor alpha (TNF-α) within the graft. It has been demonstrated that a high neutrophil-lymphocyte ratio amplifies the inflammatory process during acute renal failure [6]. Furthermore, neutrophil-depleted mice and intracellular adhesion molecule 1 (ICAM-1) knockouts are more resistant to renal ischemic injury; suggesting that neutralizing neutrophil activity could increase transplant success rates by reducing early graft damage [7]. Macrophages are also an important source of interleukin 1 (IL-1), IL-6, transforming growth factor beta (TFG-*β*), interferon *γ*-induced protein 10 (IP-10), monocyte chemoattractant protein 1 (MCP-1), and macrophage inflammatory protein 2 (MIP-2) during ischemia [8]. In the context of renal damage, monocytes are recruited within the

and patient survival.

144 Pathophysiology - Altered Physiological States

that enhances allograft damage.

**2.1. Cells of the innate immune system**

The complement system is a set of membrane-anchored and serum proteins that work in a coordinated way to eliminate microorganisms or damaged cells. The functions of complement include opsonization, inflammation through secondary products that result from the degradation of anaphylatoxins and formation of the membrane attack complex (MAC). There are three known complement pathways: the classical pathway that depends on the previous binding of antibodies, the alternate pathway that depends on the spontaneous hydrolysis and binding of C3 and the pathway of lectins that depends on the binding of proteins to carbohydrates. Currently, there is evidence to suggest the participation of the three complement pathways during renal transplantation [20–22].

**4. Immunotolerance in transplantation**

and peripheral deletional, and nondeletional mechanisms.

**4.1. Mechanisms of -cell tolerance**

and activation of regulatory T cells.

**4.2. Induction of immunologic tolerance**

The term immunotolerance implies the absence of recognition and renal graft attack by the immune cells of the recipient. One of the most important developments in the field of organ transplantation has been the use of immunosuppressive therapies that interfere with immune recognition and consequently delay graft rejection. Nonetheless, although immunosuppression is used, some immune adaptation may develop in the graft. To choose a clinically successful immunosuppressive therapy, several factors must be considered: they must be easily applicable in clinical practice, there should be enough evidence of their effectiveness, they must be stable over time even in conditions where the immune system is altered, and their mechanism of action should not have cross-reactions with other therapies. As a final point, it should be possible to measure and control its levels in the transplanted patient [30]. Induction of tolerance can occur through various mechanisms that include thymic deletional, central

Immunopathology of Kidney Transplantation http://dx.doi.org/10.5772/intechopen.70596 147

T cell tolerance in transplantation is a regulated process that ensures the tolerance and permanence of antigens, similarly to tolerance required for the maintenance of self-antigens [31]. It consists of several stages: deletion, anergy, suppression, and ignorance. Tolerance is maintained by several mechanisms initiating in the thymus, where T cells are chosen by negative selection. The main mechanism of transplanted antigens tolerance is through intrathymic deletion of donor-reactive T cells [32]. Although there are additional mechanisms of peripheral tolerance, most T cells are eliminated by this mechanism. Peripheral deletion of T cells is an important mechanism of tolerance, in which CD4 T cells reactive to donor antigens show activation, as well as apoptotic cell death. Once the tolerance is given T cells cannot respond to antigens, a state known as anergy. A costimulatory block induces anergy and has been successfully applied for tolerance induction. The activation of the T cell requires at least two signals: an antigen-dependent T cell receptor-mediated signal 1 and an antigen-independent costimulatory signal 2 [33]. CD4 and CD25 T cell regulators are actively involved in the development of immunological tolerance toward the graft. Ignorance is another mechanism that occurs when donor antigens are not recognized by the lymphoid system of the recipient or when lymphocytes fail to invade the graft. However, this mechanism applies to nonvascularized grafts. The aim of tolerance induction in renal transplantation is to block direct and indirect alloresponse pathways. In the first, it is necessary to establish the depletion of the recipient T cells and the activation of suppressor cells capable of regulating T cells. Some drugs can induce the death of alloreactive T cells. On the other hand, oral administration of allopeptides may also produce specific tolerance to corresponding alloantigens and generate specific production

Tolerance induction requires alloreactive T-cell deletion in the thymus before these cells can be released to the periphery. Hematopoietic chimerism is a widespread method to

#### **2.4. Innate-adaptive immunity interactions**

Communication between innate and adaptive immunity largely depends on antigen presentation. T and B cells express antigen-specific receptors (TCR and BCR). The signals elicited by the TCR and BCR are insufficient to achieve the proper activation state, and costimulatory molecules and cytokines provided by innate immune cells are necessary [4]. Although DCs are the most efficient APCs, neutrophils, basophils, and eosinophils also influence the outcome of adaptive immunity. Neutrophils can recruit IL-17-producing Th17 lymphocytes by releasing CCL2 and CCL20. Interestingly, patients with a history of chronic renal dysfunction showed a significant increase in IL-17 producing cells [23]. Basophils are normally activated by IL-3 or immunoglobulin binding in different renal structures; and are an important source of cytokines, thymic stromal lymphopoietin, leukotrienes and histamines which may influence the outcome of adaptive immune responses [24, 25]. Basophils express MCH Class II and are considered important regulators of T and B cell activation. Moreover, an increase in eosinophils in renal transplant, recipients has been proposed as a predictor of allograft success [26].
