**Immunopathology of Kidney Transplantation**

**Immunopathology of Kidney Transplantation**

DOI: 10.5772/intechopen.70596

Zesergio Melo, Juan A. Ruiz-Pacheco, Claudia A. Mendoza-Cerpa and Raquel Echavarria Claudia A. Mendoza-Cerpa and Raquel Echavarria

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.70596

Zesergio Melo, Juan A. Ruiz-Pacheco,

#### **Abstract**

Renal transplantation is currently the best alternative for patients with end-stage renal disease. Immune responses activated against the allograft are a decisive factor in transplantation outcomes and patient survival. Although short-term graft and patient survival have improved significantly as a result of better donor matching systems, novel immunosuppressive agents and enhanced care, long-term outcomes remain unfavorable and reflect sub-clinical injury caused by chronic rejection. The immune system lies at the intersection of immunogenic tolerance and graft failure; thus, it is a major determinant of pathology in the context of renal transplantation. During the early stages of transplantation increased expression of cytokines has been observed in addition to increased expression of adhesion proteins and immune cells. This early inflammatory response does not necessarily end in graft rejection, although this will depend on the severity of the inflammation. Activation of Toll-like Receptors (TLRs), damaging molecular patterns (DAMPs), and other components of innate immunity is key to the formation of atherosclerotic plaques and the development of autoimmune diseases. Initially the donor antigens are presented to the T lymphocytes of the recipient. This activation induces their proliferation, differentiation and cytokine production. Successful kidney transplant recipients need to develop immunologic tolerance against donor antigens. In this chapter, we address some of the innate and adaptive immune mechanisms associated with kidney transplantation; emphasizing their role in allograft rejection.

**Keywords:** kidney, transplantation, immunopathology, graft rejection, immunology

#### **1. Introduction**

According to statistics from the United States Renal Data System (UNOS) and the U.S. Department of Health & Human Services Organ Procurement and Transplantation Network

Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons

(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 and patient survival.

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

Immunopathology of Kidney Transplantation http://dx.doi.org/10.5772/intechopen.70596 145

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

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

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,

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

tissue damage, and inflammation in animals subjected to ischemia [19].

cells and are more resistant to kidney damage [10, 11].

**transplantation**

of proinflammatory cytokines [4].

**2.3. The complement system**
