**4. Immunotolerance in transplantation**

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

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

**3.1. Allorecognition, T-cell activation, T cell–mediated cytotoxicity, and B lymphocytes**

The term allorecognition refers to recognition of diverse forms of genes between a member of the same species by T cells and involve Human major histocompatibility complex (MHC) glycoproteins. MHC is a family composed by the most studied antigens in transplantation field. These antigens are widely known as human leukocyte antigens (HLA). The genes encoding HLA antigens are highly polymorphic, this feature represents a big obstacle in the study of mechanisms of graft rejection. Class I HLA are present in membranes of the nucleated cell of humans and its function is to present small endogenous antigens to CD8 T lymphocytes. Class II are expressed on dendritic cells, macrophages, B cells, endothelial, and some types of epithelial cells. This T cell recognition event is the first step of graft rejection. There are two different ways in which T cells recognize alloantigens, i.e., direct and indirect. Direct recognition is when CD8+ and CD4+ T cells from the recipient recognize MHC class I and class II presented by APCs and donor peptides. Indirect recognition is mediated by specialized APCs form the recipient presenting to T cells [27]. Donor endothelial cells express molecules that stimulate T cells, these activated cells provide help to B cells resulting in the production of alloantibodies [28]. Although the most studied role of B cells is associated with alloantibodies and donor specific antibodies, there are controversial opinions about the deleterious role of these antibodies and its

pathways during renal transplantation [20–22].

**2.4. Innate-adaptive immunity interactions**

146 Pathophysiology - Altered Physiological States

of allograft success [26].

**3. Adaptive immune responses**

association with poor graft outcomes [29].

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 and peripheral deletional, and nondeletional mechanisms.

#### **4.1. Mechanisms of -cell tolerance**

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 and activation of regulatory T cells.

#### **4.2. Induction of immunologic tolerance**

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 induce tolerance. Animal models have improved our understanding of this mechanism that ranges from tolerance induction through the injection of allogeneic cells into newborn mice to the use of adult irradiated animals injected with allogeneic donor bone marrow [34]. Tolerance induction at the peripheral systemic level needs to target mature T cells by blocking T cell molecules located on its surface, which have important roles in the activation of signaling pathways that impact cell function directly. To this end, antibodies directed against CD4 or CD8 or costimulatory molecules have been used. CD28 receptor blockade prevents proinflammatory cytokine production, as well as T cell survival and proliferation. It is also possible to interfere with the signaling pathways involved in T cell survival and proliferation, which is the case of the mTOR pathway inhibitor rapamycin. Clinical studies in humans have focused on graft tolerance induction by pretransplanting donor hematopoietic cells in human leukocyte antigen (HLA)-matched and mismatched kidney transplant recipients [35, 36].

**5. Graft rejection**

**5.1. T cell–mediated rejection**

CXCL11) release.

Current immunosuppressant therapies have drastically reduced acute rejection events in kidney transplant recipients [46, 47]. Unfortunately, there is still a high percentage of short- and long-term kidney graft loses secondary to ABMR [2]. Here, we will discuss the contribution of adaptive and innate immune cells; as well as antibodies, molecules from the complement

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T cell mediated rejection (TCMR) is characterized by infiltration of the donor graft interstitium by host CD4 and CD8 T effector and memory cells, macrophages, and dendritic cells; followed by epithelial dedifferentiation and tubulitis [48, 49] (see histopathological findings in **Figure 2**). TCMR is the predominant phenotype found in kidney transplant recipients with early rejection and it is still an important cause of graft dysfunction that when left untreated causes fibrosis, tubular atrophy, and irreversible nephron loss [50]. Genes expressed by effector T cells, APCs, and macrophages stimulated with IFN-*γ* are abundant in the transcriptomic signature of TCMR. These transcripts are mostly related to T cell receptor signaling, T helper differentiation and communication between adaptive and innate immune cells; highlighting the importance of these pathways in TCMR [51]. Cytotoxic molecules like perforin, granulysin,

**Figure 1.** Mechanisms of ABMR and TCMR in kidney transplantation. Preformed and *de novo* DSAs, complement proteins, and antibody-dependent NK cell-mediated IFN-*γ* release and cytotoxicity have emerged as key immune players in the development of the microvascular damage characteristic of ABMR. Meanwhile, in TCMR the interaction of infiltrating T cells with intragraft APCs and macrophages triggers an inflammatory response dependent on TCR synapse and subsequent activation, and characterized by chemokine (CCL5) and cytokine (CXCL9, CXCL10, and

system and chemokines to disease states that lead to kidney graft rejection (**Figure 1**).

#### **4.3. Immunosuppressive therapy in renal transplantation**

The discovery of effective immunosuppressive drugs has had great impact in the field of transplantation. Currently available immunosuppressive therapies focus on three main objectives: induction, maintenance, and treatment of rejection. For induction therapy three types of antibodies are used, the lymphocytes depleting agents, antithymocyte globulin and alemtuzumab, and basiliximab (nondepleting) [37]. Basiliximab, an IL-2 receptor antagonist and it is used in combination with other immunosuppressants, significantly reduces acute rejection in large clinical studies [38]. The use of antithymocyte antibodies in diseased donor recipients also reduces early acute rejection incidence. Nevertheless, its use has been associated with reversible leukopenia, thrombocytopenia, and cytomegalovirus infection [39].

The use of calcineurin inhibitors cyclosporine and tacrolimus has been key in reducing the risk of rejection and has greatly improved short-term graft survival outcomes. Unfortunately, in the long run they also help develop histological changes typical of nephropathy that diminish kidney graft function and increase risk of graft loss [40, 41]. A T cell costimulatory inhibitor called belatacept was introduced to avoid the deleterious effects of calcineurin inhibitors. In several studies, belatacept prevents acute rejection in renal transplantation comparable to cyclosporine [42]. Since the 1980s, several options have been developed to reduce kidney transplant rejection. Monoclonal muromonab-CD3/ OKT3, monoclonal interleukin-2 receptor (IL-2R) antibodies (daclizumab and zenapax), and antiproliferative agents (mycophenolate mofetil) are part of a large list of options currently available in renal transplantation [43]. Nevertheless, some transplant experts propose a reduction in the use of immunosuppressive drugs in order to reduce the nephrotoxicity that can also end in fibrosis and graft rejection. Additionally, some transplant recipients develop diabetes, cardiovascular disease, dyslipidemia associated to immunosuppressant therapies. For this reason, it is estimated that kidney grafts can function on average 10 years after the transplantation [44, 45].
