Unlocking the Key to Profitable Organ Transplantation: Unraveling the Complicated Mechanisms of the Main Histocompatibility Complicated (MHC) in Immune Compatibility

Unlocking the Key to Profitable Organ Transplantation: Unraveling the Complicated Mechanisms of the Main Histocompatibility Complicated (MHC) in Immune Compatibility

 

INTRODUCTION

The success of tissue and organ transplants relies on the

donor’s and recipient’s main histocompatibility advanced

(MHC) proteins, which current antigens to T cells. The MHC

proteins are alloantigens (i.e., they differ amongst members of

the identical species). In people, these proteins are encoded by the

human leukocyte antigen (HLA) genes, clustered on chromo-

some 6. (Be aware that we’ll use MHC and HLA interchangeably.)

Three of those genes (HLA-A, HLA-B, and HLA-C) code for

the category I MHC proteins. A number of HLA-D loci decide the

class II MHC proteins (i.e., DP, DQ, and DR) (Determine 62–1). The

options of sophistication I and sophistication II MHC proteins are in contrast in

Desk 62–1. If the HLA proteins on the donor’s cells differ from

these on the recipient’s cells, then an immune response happens

within the recipient.

Every particular person has two haplotypes (i.e., two units of those

genes—one on the paternal and the opposite on the maternal

chromosome 6). These genes are very various (polymorphic)

(i.e., there are various alleles of the category I and sophistication II genes). For

instance, as of 2017, there are at the very least 3900 HLA-A alleles,

4800 HLA-B alleles, 3500 HLA-C alleles, and greater than

4600 HLA-D alleles, and extra are being found. Nevertheless,

a person inherits solely a single allele at every locus from

every dad or mum and thus could make not more than two class I and

II proteins at every gene locus. Expression of those genes is

codominant (i.e., the proteins encoded by each the paternal and

maternal genes are produced).

The category I MHC proteins consist of 1 HLA-encoded

polypeptide, so every particular person can have three encoded by

paternal genes and three encoded by maternal genes for a

whole of six. Nevertheless, the category II MHC proteins include two

HLA-encoded polypeptides, so every particular person can have extra

than six as a result of the peptides can combine and match.

Along with the most important antigens encoded by the HLA genes,

there’s an unknown variety of minor antigens encoded by

genes at websites apart from the HLA locus. These minor antigens

are numerous regular physique proteins which have a number of amino

acid variations from one particular person to a different (i.e., they’re “allelic

variants”). As a result of these proteins have amino acid variations,

they’re doubtlessly immunogenic when launched as half

of the donor graft tissue. Minor antigens can induce a weak

immune response, leading to gradual rejection of a graft, or the

cumulative impact of a number of minor antigens can result in a extra

fast rejection. Predicting rejection on the premise of minor anti-

gens is troublesome, so donors and recipients aren’t routinely examined

for particular minor histocompatibility antigens. In view of those

variations in minor antigens, all recipients routinely obtain

immunosuppressive medication, even when their main histocompatibil-

ity loci are well-matched.

Positioned between the category I and sophistication II gene loci is a 3rd

locus (see Determine 62–1), generally known as class III. This locus

comprises a number of immunologically necessary genes, encoding

two cytokines (tumor necrosis issue and lymphotoxin) and two

complement elements (C2 and C4), however this locus doesn’t

have any genes that encode histocompatibility antigens.

MHC PROTEINS

Class I MHC Proteins

These are glycoproteins discovered on the floor of nearly all

nucleated cells. The entire class I protein consists of a

45,000-molecular-weight heavy chain noncovalently sure to a

β2-microglobulin. The heavy chain is very polymorphic and

is just like an immunoglobulin molecule; it has hypervariable

areas in its N-terminal area that presents the brief peptides

to T cells. The polymorphism of those molecules is necessary

within the recognition of self and nonself. Said one other method, if

these molecules had been extra comparable, our capability to simply accept for-

eign grafts can be correspondingly improved. The heavy

chain additionally has a relentless area the place the CD8 protein of the

cytotoxic T cell binds.

Class II MHC Proteins

These are glycoproteins discovered solely on the floor of profes-

sional antigen-presenting cells (APCs), resembling dendritic

cells, macrophages, and B cells (see Chapter 60). They’re

extremely polymorphic glycoproteins composed of two chains,

known as alpha and beta which might be noncovalently sure. Like class

I proteins, the category II proteins have hypervariable areas

that current the brief peptides to T cells and supply a lot

of the polymorphism. In contrast to class I proteins, which have

just one chain encoded by the MHC locus (pairing with β2-

microglobulin, encoded on chromosome 15), each the alpha

and beta chains of the category II proteins are encoded by the MHC

locus. The 2 peptides even have a relentless area the place the

CD4 proteins of the helper T cells bind.

BIOLOGIC IMPORTANCE OF MHC

The power of T cells to acknowledge antigen relies on asso-

ciation of the antigen with both class I or class II proteins (see

Chapter 60). For instance, CD8-positive cytotoxic T cells solely

reply to antigen in affiliation with class I MHC proteins. Thus,

a cytotoxic T cell that’s activated to kill a virus-infected cell will

not kill a cell contaminated with the identical virus if the cell doesn’t additionally

categorical the suitable class I proteins. (This was decided

by mixing cytotoxic T cells from particular person “A,” bearing one

set of sophistication I MHC proteins, with virus-infected cells bearing a

set of sophistication I MHC proteins from particular person “B.” Due to the

class I MHC mismatch, no killing of the virus-infected “B” cells

occurred.) This peptide–MHC requirement holds for an individ-

ual’s CD4-positive T helper cell with respect to that particular person’s

class II proteins. The requirement that antigen recognition happens

in affiliation with a “self” MHC protein is known as MHC restric-

tion and is a results of constructive thymic choice (see Chapter 59).

MHC genes and proteins are additionally necessary in two different

medical contexts. One is that many autoimmune ailments happen

in individuals who carry sure MHC genes (see Chapter 66), and

the opposite is that the success of organ transplants is, largely,

decided by the compatibility of the MHC genes of the donor

and recipient (see later).

TRANSPLANTATION

The probability {that a} transplanted organ, or graft, is accepted

by the recipient’s immune system relies on the genetic simi-

larity between the recipient and the donor. On one finish of the

spectrum, an autograft (switch of a person’s personal tissue to

one other web site within the physique) is at all times completely accepted (i.e., it

at all times “takes”). A syngeneic graft is a switch of tissue between

genetically similar people (i.e., similar twins) and virtually

at all times “takes.” On the opposite finish of the spectrum, a xenograft, a

switch of tissue between completely different species, is the least more likely to

succeed besides below sure uncommon circumstances.

An allograft is a graft between genetically completely different mem-

bers of the identical species (e.g., from one human to a different).

Allografts are often rejected until the recipient is given

immunosuppressive medication. The severity and rapidity of the

rejection will range relying on the diploma of the variations

between the donor and the recipient on the MHC loci.

Strong Organ Allograft Rejection

Even with good HLA matching, the presence of minor antigens

signifies that immunosuppression is required after a transplant to

stop allograft rejection. As HLA mismatching will increase,

extra immunosuppression is required. In acute allograft rejec-

tion, vascularization of the graft is regular initially, however, in 11 to

14 days, marked discount in circulation and mononuclear cell

infiltration happens, with eventual necrosis. That is additionally known as

a major (first-set) response. A T-cell–mediated response is

the primary reason for acute rejection of many forms of grafts, however

antibodies contribute to the rejection of sure transplants. (In

experimental animals, rejection of most forms of grafts might be

transferred by cells, not serum. As well as, T-cell–poor

animals don’t reject grafts, however B-cell–poor animals do.)

If a second allograft from the identical donor is utilized to a

sensitized recipient, it’s rejected in 5 to six days. This acceler-

ated (second-set) response is precipitated primarily by presensitized

cytotoxic T cells.

A graft that survives an acute allograft response can never-

theless bear continual rejection. This causes gradual lack of

graft perform and may happen months to years after engraftment.

The primary pathologic discovering in grafts present process continual

rejection is atherosclerosis of the vascular endothelium. The

immunologic stimulus that causes continual rejection is advanced

and multifactorial and may happen even in HLA-matched donor–

recipient pairs as a result of presence of minor histocompatibility

antigens. The adversarial results of long-term use of immunosup-

pressive medication may additionally play a job in continual rejection. Continual

rejection typically doesn’t reply to therapy, and it carries

a poor prognosis.

Along with acute and continual rejection, a 3rd kind known as

hyperacute rejection can happen. Hyperacute rejection sometimes

happens inside minutes of a strong organ transplant graft and is

as a result of response of preformed anti-ABO antibodies within the

recipient with ABO antigens on the floor of the endothelium

of the graft. Hyperacute rejection is usually known as the “white

graft” response, as a result of the graft turns white on account of the

lack of blood provide brought on by spasm and occlusion of the

vessels serving the graft. In view of this extreme rejection reac-

tion, the ABO blood group of donors and recipients should be

matched, and a cross-matching take a look at (see later) should be finished.

The laboratory checks used to find out ABO blood teams are

described in Chapter 64.

Relying on the kind of graft and the kind of rejection,

mismatching of the HLA-A, HLA-B, and HLA-DR alleles is the

most predictive of strong organ transplant rejection. The donor

alloantigens encoded by these alleles result in activation of antigen-

particular recipient helper and cytotoxic T cells. The energy of

the response to international MHC proteins might be defined by the

remark that there are two immune pathways by which the

recipient’s immune response is stimulated (Determine 62–2).

These pathways are summarized as follows and are differ-

entiated by whether or not the sensitizing APC is donor-derived or

recipient-derived:

(1) Within the direct pathway of allograft recognition, there

should be donor–recipient HLA mismatch. On this pathway, the

donor’s APCs contained throughout the grafted organ migrate to

a close-by secondary lymphoid tissue and current peptides in

affiliation with their class I and sophistication II MHC proteins. The

mere presence of the donor HLA protein that’s presenting the

peptide is sufficient to make the peptide–MHC advanced seem

to be nonself to the recipient’s T cells, whatever the peptide.

In contrast to the standard activation of T cells by cognate peptides

complexed with MHC (see Chapter 60), “direct” recognition of

these nonself HLA proteins triggers a polyclonal activation

of a a lot bigger share of recipient T-cell clones, by

some estimates as much as 10% of the recipient T cells. That is doubtless

as a result of the range of peptides complexed to the donor MHC

proteins can set off a equally various array of T-cell clones.

If the nonself HLA proteins are class I, they are going to activate CD8-

constructive T cells to turn into cytotoxic T lymphocytes (CTLs), which

infiltrate the graft and kill the graft cells as a result of they categorical the

similar class I proteins. “Direct” recognition of sophistication II HLA proteins

also can set off activation of the recipient’s CD4-positive T cells,

which might present the cytokine “assist” that enhances CD8-positive

T-cell activation, as described in Chapter 60.

(2) Within the oblique pathway of allograft recognition, the

recipient’s APCs current the donor’s proteins. The donor’s pro-

teins which might be shed by broken cells of the graft are taken up by

recipient dendritic cells, processed, and introduced to T cells as

“international” proteins in a draining lymph node. (If there’s HLA

mismatch, the donor HLA proteins are sometimes the antigens

chargeable for this pathway as a result of HLA proteins are extremely

polymorphic and immunogenic. However even with out HLA mis-

match, there are minor antigens that may carry concerning the indi-

rect pathway of rejection.) This ends in activation of

CD4-positive helper T cells (see Chapter 60). The newly

activated T helper cells can (a) migrate again to the graft and

activate macrophages (Th-1 cells) and (b) recruit neutrophils

(Th-17 cells), or (c) migrate to the B-cell follicle and induce

antibodies towards the graft cells). Be aware that if the donor and

recipient aren’t matched on the class I HLA loci, then the indi-

rect pathway can not contain cytotoxic T cells. Recipient cyto-

poisonous T cells activated via the oblique pathway will solely be

capable of acknowledge peptides introduced on “self ” HLA proteins,

whereas these within the graft shall be “nonself.”

In contrast with the direct pathway, the oblique pathway

takes longer as a result of the recipient dendritic cells must enter

the graft, take up HLA proteins, and migrate to the draining

lymph node to activate the adaptive immune response. Additionally, as

time passes, the graft’s donor APCs are regularly changed by

recipient APCs, and the chance of direct recognition being a mecha-

nism for rejection declines. Subsequently, whereas each the direct

and oblique pathways can contribute to acute rejection, the

oblique pathway is primarily chargeable for continual rejection.

In all rejection eventualities, the activation of T cells should

be accompanied by inflammatory stimuli, resembling pathogen-

related molecular patterns (PAMPs) and damage-associated

molecular patterns (DAMPs). These are essential to induce the

co-stimulatory indicators, resembling B7 molecules, on the APCs in

order to completely activate the T cells (see Chapter 60). That is clini-

cally related as a result of limiting irritation and tissue injury

on the time of transplantation considerably limits the probability

of graft rejection and improves outcomes. This explains why

transplant surgeons drastically choose to transplant organs from reside

donors each time potential.

Hematopoietic Stem Cell Transplants

Malignancies of the hematologic system, notably leukemia,

are sometimes handled with transplant of hematopoietic stem cells.

The precept of this strategy is to make use of aggressive chemo-

remedy to ablate all the affected person’s hematopoietic cells, which

consists of many of the malignant cells, after which substitute them with

wholesome stem cells that may repopulate the hematopoietic system

(see Determine 58–1). Prior to now, these transplants had been known as

“bone marrow transplants” as a result of the stem cells had been remoted

from bone marrow aspirates, however now the stem cells can be

derived from leukopheresis of peripheral blood or from a pattern

of banked umbilical twine blood.

In contrast to most strong organ transplants, transplanted hemato-

poietic stem cells might be autologous (from the affected person’s personal stem

cell pool) or allogeneic (from a donor). Autologous cell trans-

vegetation are safer and keep away from the necessity to discover a matched donor,

so that you may assume this could be the popular strategy in all

instances. Nevertheless, the primary benefit to utilizing allogeneic cells is

that when these cells engraft, the T cells will really assault any

surviving malignant cells. This graft-versus-malignancy impact

can happen with HLA-matched or -unmatched stem cells as a result of

of the minor antigens acknowledged by the donor cells. With out

this impact, autologous transplants have greater relapse charges.

Graft-Versus-Host Response

As described earlier, one of many main benefits of allogeneic

stem cell transplants is that the transplanted cells assault the

malignant cells, even in well-matched donor–recipient pairs.

An unlucky adversarial impact in these transplants is that trans-

planted cells might subsequently assault host cells. This graft-

versus-host (GVH) response develops in about two-thirds of

the recipients.

This response happens as a result of grafted immunocompetent

T cells proliferate within the irradiated, immunocompromised host

and reject host cells with “international” proteins, leading to extreme

organ dysfunction. The donor’s cytotoxic T cells play a serious

function in destroying the recipient’s cells. These reactions happen

primarily in “barrier tissues,” such because the pores and skin and gastroin-

testinal system, inflicting extreme rash, oral ulcers, diarrhea, and

hepatitis. Many GVH reactions finish in overwhelming infections

and demise.

There are three necessities for a GVH response to happen:

(1) the graft should comprise immunocompetent T cells, (2) the

recipient should be immunocompromised, and (3) the recipient

should categorical antigens (e.g., MHC proteins) international to the donor

(i.e., the donor T cells acknowledge the recipient cells as international).

Be aware that, just like the graft-versus-malignancy impact, even when

donor and recipient have similar class I and sophistication II MHC pro-

teins, a GVH response can happen due to variations in minor

antigens. Danger of GVH reactions might be lowered by depleting

the donor cell pool of T cells earlier than the transplant, however this

additionally reduces the graft-versus-malignancy impact and due to this fact

will increase relapse charges.

As soon as it happens, GVH is handled with immunosuppressive

brokers (see under). Though these medication suppress the allograft

response, most sufferers should take these medication for his or her total

lives. Immunosuppression will increase the chance of illness relapse

(by limiting graft-versus-malignancy impact) and in addition will increase

the chance of creating different malignancies in addition to opportunis-

tic infections.

HLA Typing within the Laboratory

Previous to transplantation, laboratory checks, generally known as

HLA typing or tissue typing, are carried out to find out the

closest MHC match between the donor and the recipient. The

most necessary alleles to match are HLA-A, HLA-B, HLA-C,

HLA-DR, and HLA-DQ, and a donor–recipient pair through which all

10 of the maternal and paternal alleles of those 5 genes match

is known as a “10/10 match.” Prior to now, serologic assays had been used

to find out the Class 1 and Class II MHC proteins of the

donor and recipient. Nevertheless, serologic assays have now been

largely changed by DNA sequencing utilizing polymerase chain

response (PCR) amplification. DNA sequencing determines

the completely different alleles carried by donors and recipients with nice

accuracy right down to the molecular degree.

Along with the checks used for matching, preformed cyto-

poisonous antibodies within the recipient’s serum reactive towards the

graft are detected by observing the lysis of donor lymphocytes

by the recipient’s serum plus complement. That is known as cross-

matching and is completed to forestall hyperacute rejections from

occurring. In strong organ transplants, the donor and recipient

are additionally matched for the compatibility of their ABO blood

teams. The laboratory checks used to find out ABO blood

teams are described in Chapter 64.

Amongst siblings in a single household, there’s a 25% probability for

each haplotypes to be shared, a 50% probability for one haplotype to

be shared, and a 25% probability for no haplotypes to be shared. For

instance, if the daddy is haplotype AB, the mom is CD, and

the recipient baby is AC, there’s a 25% probability for a sibling to

be AC (i.e., a two-haplotype match), a 50% probability for a sibling

to be both BC or AD (i.e., a one-haplotype match), and a 25%

probability for a sibling to be BD (i.e., a zero-haplotype match).

The Fetus Is an Allograft That

Is Not Rejected

A fetus has MHC genes inherited from the daddy which might be for-

eign to the mom, but allograft rejection of the fetus doesn’t

happen. That is true regardless of many pregnancies from the identical

mom–father mixture that produce offspring with the

similar MHC haplotypes. The explanation that the mom fails to

reject the fetus is unclear. The mom kinds antibodies towards

the international paternal MHC proteins; due to this fact, the reason being not

that the mom isn’t uncovered to fetal antigens. Some potential

explanations are (1) that the placenta doesn’t permit maternal

T cells to enter the fetus and (2) the T cells throughout the placenta

are biased towards the T-regulatory subset, which promotes

tolerance of fetal antigens (see Chapter 60).

EFFECT OF IMMUNOSUPPRESSION ON

GRAFT REJECTION

To cut back the rejection of transplanted cells or to deal with graft-

versus-host illness, immunosuppressive measures are typically

required (Desk 62–2). These fall below the classes of corti-

costeroids, DNA synthesis inhibitors (azathioprine, methotrex-

ate, mycophenolate), calcineurin inhibitors (cyclosporine and

tacrolimus), mammalian goal of rapamycin (mTOR) inhibi-

tors (sirolimus), signaling blockade (belatacept, basiliximab,

and so on.), and cell-depleting antibodies (antithymocyte globulin).

Corticosteroids bind to glucocorticoid receptors that

end in altered gene transcription in a wide range of cell sorts.

In immune cells, steroids act by inhibiting synthesis of leukotri-

enes, prostaglandins, and cytokines (e.g., IL-2) and by inducing

apoptosis of quickly dividing T cells. Corticosteroids inhibit

cytokine manufacturing by blocking transcription elements, such

as nuclear factor-κB and AP-1, which prevents the mRNA for

these cytokines from being synthesized. Glucocorticoid receptors

are present in almost each cell within the physique, inflicting widespread

off-target adjustments in gene transcription. Subsequently, the most important

drawback of corticosteroids that limits their continual use is

that they’ve quite a few adversarial endocrine, neuropsychiatric,

metabolic, and cardiovascular unwanted effects.

Azathioprine (which is transformed to 6-mercaptopurine in

the physique), methotrexate, and mycophenolate mofetil inhibit

completely different features of the nucleotide synthesis and metabolism,

shutting down DNA synthesis and thereby blocking T-cell pro-

liferation. Methotrexate may additionally have a wide range of different results

on cell signaling via inhibition of signaling enzymes.

Cyclosporine prevents the activation of T lymphocytes by

inhibiting the synthesis of interleukin (IL)-2 and IL-2 receptor.

It does so by inhibiting calcineurin—a phosphatase enzyme

that’s activated by calcium flux following binding of the T-cell

receptor, step one within the cascade that in the end results in

transcription of the genes encoding IL-2 and the IL-2 receptor.

Tacrolimus binds a special protein (FKBP1A) however has an identical

impact on calcineurin. Thus, cyclosporine and tacrolimus inhibit

one of many earliest steps within the first part of T-cell activation.

Sirolimus inhibits sign transduction via mTOR,

which is primarily concerned in sign transduction downstream

of IL-2. Subsequently, sirolimus inhibits later steps within the second

part of T-cell activation, in a pathway completely different from that of

cyclosporine and tacrolimus. These medication are extra selective

than steroids and due to this fact have fewer toxicities.

A wide range of recombinant proteins, small molecules, and

monoclonal antibodies can be utilized in immunosuppressive regi-

mens, each to forestall rejection and to deal with rejection episodes.

Belatacept is a fusion protein consisting of cytotoxic T lympho-

cyte antigen-4 (CTLA-4) fused to the Fc fragment of human

IgG. CTLA-4 competes with CD28 for binding to B7 proteins,

however does so with greater affinity, thereby blocking co-stimulation

of T cells and stopping graft rejection. Muromonab (OKT3)

was the primary authorized monoclonal antibody. It a mouse anti-

physique towards CD3 that blocks sign transduction via the

T-cell receptor. Basiliximab is a chimeric monoclonal antibody

that blocks the IL-2 receptor, stopping T-cell proliferation.

Antithymocyte globulin (ATG) is a polyclonal cocktail of

horse (Atgam) or rabbit (Thymoglobulin) antibodies towards

human thymocytes. ATG comprises antibodies towards many

lymphocyte antigens (e.g., CD3, CD4, CD8, and others).

After binding to their targets on the surfaces of T cells, these

antibodies result in cell demise via complement-mediated

lysis of the cell (amongst different potential mechanisms). As a con-

sequence, ATG has a broader immunosuppressive impact than

do the extra focused monoclonal antibodies described within the

earlier paragraph.

Sadly, immunosuppression drastically enhances the

recipient’s susceptibility to opportunistic infections and neo-

plasms. For instance, some sufferers present process therapy for

a number of sclerosis with the monoclonal antibody natalizumab

developed progressive multifocal leukoencephalopathy (see

Chapter 44 for an outline of this viral illness). The inci-

dence of most cancers is elevated as a lot as 100-fold in transplant

recipients who’ve been immunosuppressed for a very long time.

Widespread cancers in these sufferers embrace squamous cell car-

cinoma of the pores and skin, adenocarcinoma of the colon and the lung,

and lymphoma.