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Major Histocompability Complex was initially discovered for their role in transplantation and responses to tumours, showing them as genetically vital in regulating immune responses (Shi et al., 2008). MHC in reality refers to a region of DNA spanning of 4 million base pair, and contains over 100 genes (figure 1.)
MHC genes are separated into three classes based on the proteins they encode, class I, class II and class III. The class III encodes immune components proteins like complements (C4, C2) that are involved in structure of membrane attack complex (MAC) (Male et al., 2006). In contrast, class I and class II encodes proteins are expressed on cell surface and are involved in presenting wide range of foreign antigens (in peptide form) to the T cells receptors (TcR) of the T cells. Recognition of this peptide by the T cells raises an immune reaction, which accordingly destroys the peptide (Male et al., 2006) (figure 2 and 3 below): this is the basis of graft rejection in transplantation.
Figure 2: as seen above class 1 molecule is a single alpha chain (Î±1 Î±2 Î±3) that complex with beta-2 microglobulin (beta-chain), which is encoded by a gene outside the MHC complex. In disparity , the classÂ II gene is a heterodimer chain that includes one alpha- and one beta-chain polypeptide which correlate together to form the classÂ II antigens. (Wood, 2006)
Figure 3: Showing the peptide binding site role of both MHC class I and class II molecules
A Schematic overview of MHC class I (left) and MHC class II (right) antigen presentation pathways.
Figure 3: This shows how intrinsic antigens ( viral antigens in peptides forms) are presented to the T cells by the class I molecule, whereas extrinsic antigens are presented by class II MHC molecules, by working together with specific TcR ( CD4+ and CD8+) of the T cells correspondingly. Class I HLA molecules are expressed in all nucleated cells whilst class II molecules are expressed on a limited group of lymphoid/ myeloid origin (dendritic cells, B cells, macrophages). Bearing in mind that these molecules are expressed in nearly all the cells of the body means that it will be implausible for foreign antigen to escape immune surveillance of the MHC antigens (Wood, 2006). Nevertheless this beneficial role of MHC antigens (figure 3) has been an obstacle to successful organ transplantation (Male et al., 2006).
Importance of MHC in graft rejection after organ transplantation
The clinical importance of the function of MHC antigens is realized in organ transplantation (Male et al., 2006).Routinely, Cells and tissues are transplanted as a treatment for a number of terminal diseases. For example: liver failure (liver transplantation), Diabetes (pancreas transplantation) and Leukaemia (Bone marrow transplantation). There are four major kinds of transplantation (table 2.).
Table 2: Showing the types of transplantation
Types of transplantation
Procedure (transferring tissues from one place to another)
Tissues/ organ from one part of the body to another e.g. Trunk to arm. Skin graft is common after burnt.
Between genetical identical individual e.g monozygotic twins or within an inbred strain
Between members of different species e.g. monkey to man.
Between different members of the same species.
(Male et al., 2006)
Both HLA molecules have been identified to be the major antigens that are recognised as foreign antigens by the T cells because they are highly polymorphic molecules than minor histocompability complex (Male et al., 2006). Each allele varies by the changes in the amino acid of the HLA chains (Î± or Î²) and this is known as the polymorphism (table 1.) (Dyall et al, 2000). Consequently to find individuals who share comparable genes at each MHC loci in the population prior to allotransplantation is very rare.
Table 1: Thowing the Polymorphic alleles of Class I and Class II HLA
Class I molecules alleles
Class II molecules alleles
(Dyall et al., 2000).
The recognition by recipient T lymphocytes of allogeneic MHC molecules on transplanted cells known as allorecognition elicits a strong immunological reaction resulting in swift elimination of donor cells and the rejection of the graft (Gould at al., 1999). This immunological reaction is thought to be greater than the ones that are evoked against pathogens (Male et al., 2006). This could be due to the release of several cytokines such as IL-2 from the T cells receptors (CD8 & CD4 respectively) following allorecognition which are all powerful inflammatory mediators (Male et al., 2006). Graft rejection remains the stumbling block to successful large scale and long term engraftments in patients.
Table 4: Showing the cause of different types of grafts rejections.
Type of rejection
Days - weeks
Months - years
Preformed anti-donor antibodies and complement.
Reactivation of sensitized T cells
Primary activation of T cells
Causes unclear: antibodies, immune complexes, slow cellular reactions, recurrence of disease.
Taking from: (Wood, 2006)
Though the mechanisms and pathology of the different forms of graft rejection (as shown above) is not obvious (Gould et al., 2006), nevertheless there are two major allograft pathways that have been clarified over the past years that distinguish graft rejection from other kinds of immune responses (figure 4.) (Gould et al., 1999).
Figure 4: Showing the direct and indirect pathways of allograft rejection
Taking from: (Wood, 2006)
Figure 4: Direct and indirect pathways for presentation of alloantigens in vitro and in vivo. CD4+ T cells recognizing alloantigens in intact or processed forms contribute to the rejection process by providing help to CD8+ cytotoxic T cells and alloantibody-producing B cells.
HLA class II antigens are the main allogenics that have been observed in both direct and indirect pathway of the allograft rejection (Male et al., 2006). Researches show that lymphocytes from one donor, when cultured with those from a unrelated donor, are stimulated to proliferate. It has been determined that this proliferation is mainly due to a disparity in the class II MHC (DR) antigens and T cells of one individual interact with allogeneic class-II MHC antigen presenting cells (APC. i.e. dendritic cell). This reactivity is known as mixed leukocyte reaction (MLR) and has been used for studying the degree of histocompatibility (Wood, 2006) .Having said, some tissues in the body can be transplanted without match for HLA genes prior to allotransplantation (donor and recipients), and without graft rejection. Such tissues are known as immunologically privileged tissues; corneal graft is an exceptional example that enjoys the utmost success rate of any type of organ transplantation (Male et al., 2006). The best reason could be because it has a low concentration of dendritic cells (has high HLA antigens profile) in the centre. It may also have an immunosupression mechanism like Fas ligand that kills any immune cells that could come in contact with these graft tissues (Male et al., 2006).
A Study from Gould et al., (1999), signifies that MHC tissue typing is also statistically vital in the survival of some categories of organ transplants in immunosuppresed patients (Gould et al., 1999). likewise Shi et al., (2002) which used a vascularised organ transplants in pigs without immunosupression also showed that matching for MHC class I antigens prolonged graft survival (shi et al., 2002). Duijvestijn et al., (2002), studies shows that matching for MHC class II antigens allowed the indefinite survival of kidneys in about 33% of the recipients (Duijvestijn et al., 2002).when all the studies are taken together, it suggest that MHC matching is crucially important in order to avoid the initiation of direct and indirect allograft rejection pathways that frequently leads to the different grafts rejection of different organ transplantation. (George et al 1995)
Unfortunately, HLA matching in the population is rarely perfect between unrelated donors even with the recent use of polymerase chain reaction (PCR) techniques available, this is due to the matching difficulty in matching all MHC I and class II gene loci and the high level of polymorphism at each locus (Wood, 2006). This has been an obstacle to successful large scale and long term engraftments in patients (Male et al., 2006). Though cyclosporine (immunosuppressant drugs) have been known to obstruct the direct pathway, nevertheless this can only prevent acute rejection and it's linked with drug related complications like neoplasia and infection (Male et al. 2006).These drugs are still prescribed to patients in spite of the chronic side effects and this has resulted in more serious issue such as lack of donor organs. Xenotransplantation is one of the current alternatives intended to address the insufficient organ donor.
Recent development in xenotransplantations
Xenotransplantation provides a potential resolution to the severe shortage of allogeneic organs, a key limiting factor in clinical organ transplant (Male et al., 2006). The transplant of animal organ as donor into animal of different species (recipient) is known as xenotranplantation. (Roger et al 1998) For example pig organs to human.
The two major sources for xenotransplantation were pigs and non human primates (NHPs) (Yang et al., 2007). NHPs was the first choice because they are closely related and physogenically and immunologically alike to humans (Louz et al., 2007), NHPs have been rejected by scientists as animal dono for the following relative issues; they have small anatomical size, their use is linked with the risk of donor pathogens infections for humans, limited availability and ethical considerations (Yang et al., 2007).
Currently the most suitable donor animal sources are pigs. This is based largely on the fact that pigs have both anatomical and physiological similarities with humans such as the circulatory system, size of the organs and they are easily available in large number, because they have relatively short reproduction cycle and large litter sizes (Male et al, 2006). Also pigs can be bred in genetically homogenous precise pathogen free herds and kept readily controlled in an hygienic environment at comparatively low cost (Yang et al, 2007).The use of this animal donor would have made humans transplants waiting list for different organ transplants to diminish considerably.
Regrettably, there are numerous obstacles to overcome before xenotransplantation of porcine can become clinically applicable to human (Schiwinzer et al, 2008). The main hindrance that scientists have noticed to be the most worrying of using xenografts are the immunological rejection, and the fear of cross species infection of human recipients upon contact with the graft, while the main anxiety being the transmissions of porcine endogenous retrovirus (PERV) which are found in pig genome in the multiple copies (Schiwinzer et al, 2008). In combining, the moral issues that have been raised against implants of porcine into humans body. All these issues represent a shortfall to xenotransplatation research (Louz et al, 2007)
Presently, scientist observed that human decaying factor (hDAF) which is also known as CD55 and CD59 can down regulate the pathway of complement activation and thus has ability to reduce hyperacute rejection to the organs from transgenic pigs (Schiwinzer et al 2008). In ex vivo perfusion studies show that hyper acute was prevented in the kidney, lung and heart of the transgenic pigs introduced with a gene encoding hDAF or CD59 (Schiwinzer et al, 2008). Studies demonstrate that expression of a functional human CD59 on cardiac endothelium of atransgenic pig hinders the formation of membrane attack complex (MAC i.e., C5b - C8 complexed with C9 epitopes) and reduces damages occurring on the heart tissues of a baboon, to which the heart of a transgenic pig has been transplanted. additionally, Cozzi et al, (2002), later established that transplantation from the heart and kidney from an hDAF transgenic pig to non human primates recipients allows the recipients to sustain a lifelong of over 30days and 78days respectively (cozzy et al., 2008) . In the light, hDAF or CD59 transgenic pig is likely to aid long term graft survival by conquering hyperacute rejection.
As a result of preformed anti - Î± - galactosyl antibodies in the recepients' circulation, a pig organ transplanted into human will undergo hyperacut rejection (male et al., 2006; Louz et al., 2007). One solution is to engineer pigs by nuclear cloning from cell lines that do not have the galactosyl tranferase enzyme accountable for creating Î± - galatosyl residues. Several studies at present shows that organs derived from engineered pigs showed realistically long term survival in primates (Male et al 2006, Schiwanzi et al., 2007).
Finally, the apprehension that xenotransplantation can transmits extensive array of pathogens have been lessened, since several exogenous viruses can be eliminated by SPF breeding or vaccination of source animals and adequate screening with of the xenografts before transplantation (Louz et al., 2008). Nevertheless, studies have failed to show a means to screen and to eliminate the main risk passed by the PERVs which are present in the pigs' genome in multiple copies. However I believe the current molecular techniques such as Real -Time polymerase chain reaction (RTPCR), should be able to allow screen for the PERVs before xenotransplantation. (Klymiuk et al 2009)
It is now accepted that MHC plays a key role in graft rejection in allotransplantation and has accordingly triggered the use of immunosuppressant drugs like corticosteroids which have caused severe side effects and the need of organ donor. More significantly graft rejection is an obstacle to the success of any type of transplantations. If broader studies can be carried out without considering the ethical believes, it should be noted that xenotransplantation could have been a promising donor source as it can be observed that even with the little ongoing research there are current developments that are encouraging for the need of xenotransplantation. Therefore, the funding of extensive studies is advisable so that xenotransplantation can be of clinical use. If transgenic pigs could be made available, it will offer excess donors for use which solves the predominant problem in transplantation without the need of immunosuppressant drugs. Having said, stem cell therapy and mixed chemirism are some encouraging developments in transplantation (Male et al., 2006).