the primary function of the immune system is to protect the host from infectious microbes in its environment . this system has evolved over millions of years , in response of coexistence with microorganisms . basically , the system can be divided in two components , the innate and adaptive immunities . the innate also called natural 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 ( amps ) . this response is phylogenetically older in comparison to the adaptive immunity , which involves recognition of specific antigen , conferring both specificity and a memory effect . t cells recognize antigen in the form of peptide bound to major histocompatibility complex ( mhc ) molecules . b cells have immunoglobulin receptors that recognize the antigenic portions of determined molecules . in organ transplantation , the adaptive immunity is considered the main response exerted to the transplanted tissue , since the principal target of the immune response is the mhc molecules expressed on the surface of donor cells . however , we should not forget that the innate and adaptive immunities are divided only by educational purposes , since both are codependent . for example , t - cell activation leads to the production of cytokines and chemokines which in turn may recruit components of the innate immunity like nk cells or macrophages . furthermore , local tissue production of complement components seems to be essential for full t - cell activation , and some amps like defensins and cathelicidin have chemoattractant properties on t lymphocytes . because the immune system uses many different effector mechanisms to destroy the broad range of microbial cells and particles that it encounters , it is critical for the immune response to avoid unleashing these destructive mechanisms against its own tissues . this avoidance of destruction of self - tissues is referred to as self - tolerance . mechanisms to avoid reaction against self - antigens are expressed in many parts of both the innate and the adaptive immune responses . unfortunately , transplanted tissues from individuals of the same species ( allogenic ) or different species ( xenogeneic ) are recognized as nonself , causing graft rejection . the process by which the immune system recognizes pathogens , tumors , and transplantation antigens involves the same antigen recognition molecules . the rejection response to grafted tissue is caused by cell surface molecules that induce an antigenic stimulus . a wide variety of transplantation antigens have been described , including the mhc molecules , minor histocompatibility antigens , abo blood group antigens , and monocytes / endothelial cell antigens . the minor histocompatibility antigens are processed peptides derived from cellular antigens that are presented by mhc molecules but are not derived from the mhc . however , abo incompatibility can result in hyperacute rejection of primarily vascularized grafts , such as kidney and heart . as we mentioned before , the principal target of the transplantation immune response is the mhc molecules expressed on the surface of donor cells . according to their relative potencies in eliciting rejection , the major antigens in mammalian species are encoded by a closely linked series of genes called mhc . in humans , these genes reside in the short arm of chromosome 6 ( figure 1(a ) ) . organs transplanted between mhc identical individuals are readily accepted , whereas organs transplanted between mhc antigen - mismatched individuals are rejected in the absence of immunosuppressive therapy [ 8 , 9 ] . since the mhc was first defined in mice by gorer and snell [ 10 , 11 ] , the world health organization nomenclature committee has named hla ( human leukocyte antigen ) to the human mhc . the hla complex genes and their protein products have been divided into three classes ( i , ii , and iii ) on the basis of their tissue distribution , structure , and function [ 13 , 14 ] . mhc class i and ii genes encode codominantly expressed hla cell surface antigens , and class iii genes encode several components of the complement system ; all share important roles in immune function . class i mhc antigens are present on all nucleated cells and are composed of a 45-kd transmembrane  heavy chain encoded by genes of the hla - a , hla - b , or hla - c loci on chromosome 6 ; the  heavy chains are associated noncovalently with a 12-kd protein , 2-microglobulin , encoded by a gene on chromosome 15 ( figure 1(c ) ) . additional ( nonclassical ) class i molecules , like those encoded by the hla - e , -f , -g , -h loci , have been described and show limited variability and tissue distribution . the precise functions of these molecules are not yet clear , although they have been implied in presenting carbohydrate and peptide fragments to  t cells and mother 's immunological tolerance of the fetus [ 1417 ] . mhc class ii antigens are expressed only on b lymphocytes , activated t lymphocytes , monocytes , macrophages , langerhans cells , dendritic cells , endothelium , and epithelial cells . class ii molecules are heterodimers composed of noncovalently associated  and  polypeptide chains chains encoded by genes of the hla - d region ( figure 1(b ) ) . there are 3 major class ii proteins designated , hla - dp , hla - dq , and hla - dr . class iii genes are located between the hla - b and hla - d loci and determine the structure of three components of the complement system : c2 , c4 , and factor b [ 13 , 19 ] . class i mhc molecules present cytoplasm - derived peptides , or intracellular parasites , principally viruses ; whereas mhc class ii molecules bind peptides derived from extracellular proteins . hla class i and ii molecules are recognized by cd8 and cd4 positive t cells , respectively [ 2022 ] . also , nk cells may recognize hla classical and nonclassical type i molecules [ 2325 ] . hla genes are almost always inherited together , thus the antigens of the entire hla region inherited from one parent collectively are called haplotype . because chromosome 6 is an autosome ( a chromosome with two pairs ) , all individuals have two hla haplotypes ( one for each chromosome ) . according to this , any sibling pair has a 25% chance of inheriting the same two parental haplotypes , a 50% chance of sharing one haplotype , and a 25% chance of having two completely different haplotypes . since the biologic function of the hla molecules is presenting endogenous and exogenous antigens , they manifest high structural polymorphism . until 2010 , mutations in microbial antigens might permit the microbe to avoid binding ( and , consequently , recognition ) by a few hla alleles , but no mutations will permit the microbe to avoid recognition broadly throughout the population ; assuring then , the continuity of species in the presence of pandemic infection . in transplantation immunology , the major impact in graft loss comes from the effects of hla - b and -dr antigens . hla - dr mismatch effect is the most important in the first 6 months after transplantation , the hla - b effect emerges in the first 2 years , and hla - a mismatches have a deleterious effect on long - term graft survival [ 2832 ] . the phenomenon by which the recipient immune system reacts with donor antigens that are considered to be  non - self  is named allorecognition . the main and strongest responses to alloantigens are mediated by host t cells , which recognize peptide antigens presented in the context of mhc , by antigen - presenting cells ( apcs ) . however , evidence that the innate alloimmunity has an important role in graft rejection has recently been proposed by land and coworkers [ 33 , 34 ] . they state in their  injury hypothesis  that initial allograft injury reflected by reactive oxygen species ( ros ) during reperfusion is associated with generation of damps ( meaning damage - associated molecular patterns ) such as heat shock proteins ( hsp ) and hyaluronan fragments ( fha ) among others , all of which are recognized by tlr4 and/or tlr2 . subsequent tlr4- and tlr2-triggered signaling pathways utilize adaptor proteins including myd88 ( myeloid differentiation marker 88 ) , which in turn initiate downstream signaling pathways that lead to activating the 3 master transcription factors nf-b ( nuclear factor - kappa b ) , ap-1 ( activator protein-1 ) , and irf-3 ( interferon regulatory factor 3 ) . nf-b seems mainly to be responsible for maturation of donor - derived and recipient - derived dendritic cells , which represents the bridge to development of an adaptive alloimmune response that results in rejection . certainly , further studies are needed to determine the extension and importance of this branch of the immune system in transplant rejection and/or tolerance . in adaptive allogenic immune response , the foreign or donor antigen presentation to t cells may occur by three ways ( figure 2 ) : ( 1 ) indirect recognition : donor 's hla molecules can be processed by apc ( antigen presenting cells ) from a receptor , then they are fractionated into peptides as well as other bacterial antigens and are presented according to the same route as the hla in the receptor . this type of mechanism has a dominant role in chronic rejection [ 3741 ] ; ( 2 ) direct recognition : the donor 's hla molecules can be recognized directly on the donor - presenting cells , without requiring antigen processing by receptor . in these circumstances , it could be said that the receptor identifies the foreign hla molecule as an own molecule with a foreign peptide . this mechanism determines a strong immune response in the acute rejection [ 37 , 38 , 4250 ] ; ( 3 ) a third mechanism could be mediated by immunoglobulin - like receptors of natural killer ( nk ) cells . in this mechanism , the activation of nk receptors promotes the inactivation of nk cells and cytotoxic t lymphocytes as well . these receptors recognize polymorphic sequences of hla - c , -b , or -a in the target cells . the absence of these sequences in the cell would make them sensitive to cytolysis and therefore the loss of tolerance [ 5156 ] . recently , it was shown that both nave and memory cd4 and cd8 t cells are frequently cross - reactive against allogeneic hla molecules and that this allorecognition exhibits exquisite peptide and hla specificity . such advances in the understanding of the immunogenetics of allorecognition have led some researches to suggest a new model for allorecognition whereby the majority of t cell alloresponses may occur via direct recognition ( cross - reactivity ) by thymically educated nave and memory t cells against allogeneic hla molecules presenting self - peptides . according to this model , thymically educated t cells are commonly and specifically allo - hla reactive and are activated by viral infection or vaccination to become alloreactive memory t cells which are a major barrier to successful tolerance . to support the transplant programs , several clinical laboratories perform various hla tests , including hla typing of the recipient and the donor , screening of hla antibodies in the recipient , and detection of antibodies in the recipient that are reactive with lymphocytes of a prospective donor ( cross - matching ) . historically , hla typing was conducted by serologic testing by using antiserum in complement - dependent cytotoxic assays . recently , more precise dna - based hla typing methods using molecular techniques , such as sequence - specific oligonucleotide probe hybridization , sequence - specific primer amplification , sequencing - based typing , and reference strand - based conformation analysis , have been developed and are frequently used . there is a clear relationship between the degree of hla matching and kidney graft survival in transplants from living - related donors . simultaneous analysis of 5,262 one haplotype - matched living - related allografts , and 973 hla identical allografts showed 10-year projected survival rates of 52% and 73% and graft half - lives of 11.9 and 23.6 years , respectively . conversely , the influence of hla matching on the survival of liver and thoracic organs is yet uncertain . to avoid hyperacute rejection , it is very important to identify recipient anti - hla antibodies to antigens expressed on donor with blood cells . the pioneer method to detect such antibodies , the complement - dependent cytotoxicity ( cdc ) , has been gradually replaced by more - sensitive solid - phase assays , such as the enzyme - linked immunosorbent assay and the bead - based technology ( i.e. , flow cytometry : flowpra and flow analyzer : luminex ) . however , the new techniques have been associated with decreased specificity , and some non - hla antigens with no clinical relevance have been able to give a positive crossmatch . these  false - positive  antibody results have as a consequence a decreased chance of the patient to receive an organ by way of exchange organizations , thus decreasing chances for the patient . thus , the experts recommend that the information these tests provide should complement that of the direct cdc assay . development of the field of organ and tissue transplantation has accelerated remarkably since the human major histocompatibility complex ( mhc ) was discovered in 1967 . however , has been elusive avoid the graft rejection . this is due to that the transplantation immunobiology is very complex , because of the involvement of several components such as antibodies , antigen presenting cells , helper and cytotoxic t cell subsets , immune cell , surface molecules , signaling mechanisms , and cytokines , which play a role in innate and adaptive immunities .