The Major Histocompatibility Complex Transplantation Notes

Transplantation

The field of HLA and clinical transplantation are quite closely interlinked and have grown together since 1950s. According to the genetic relationship between donor and recipient, transplantation of tissues/organs is classified into 4 groups:

Read And Learn More: General Pathology Notes

Comparative Features Og MHC class L and Class II gene molecules:

• An autograft is a graft in which the donor and recipient are the same individual.
•  Isograft is a graft between the donor and recipient of the same genotype, for example, Identical twins.
• An allograft is one in which the donor is of the same species but of a different genotype.
• Xenograft is that in which the donor is of a different species from that of the recipient.
• All types of grafts have been attempted in human beings.

However, xenografts are rejected invariably due to major genetic disparity, while the most commonly performed are allografts. Survival of allograft is highest when the donor and recipient are HLA-identical.

Hla Match-Mismatch

The major role in allograft match or mismatch between donor and host is played by class I and class II loci of HLA due to the activation of antigenic receptors on the host

• T cells against donor allograft due to alloreactivity i.e. anti-graft T cell response. Even shared class I molecules between host and donor may incite.
• T cell response due to genetic differences at non-MHC loci between the non-identical donor and host i.e. minor histocompatibility loci.

Common Transplants

Tissue and organ transplantation has been possible for a vast number of tissue types: skin, bone marrow, kidney, heart, heart valves, lungs, liver, pancreas, intestines, cornea, bones, tendons, ligaments, veins, etc.

But most commonly practiced are:

• Skin grafting
• Organ transplantation of kidney and liver
• Cell transplants of bone marrow and
• Transplants of musculoskeletal tissues.

Donor Types

There are major ethical and legal issues involved in organ and tissue transplantation.

In general, there are two types of organ donors:

• Living donor: In this, the donor is live and donates renewable tissue ( for example, skin), an organ from paired organs ( for example, Kidney), or part of an organ ( for example, Part of a liver, lobe of the lung, part of intestines), or cells ( for example, Bone marrow) for transplantation.
• Deceased or cadaveric donors: These donors are further of two types:
  • Brain-dead:  individuals as declared by the treating team of doctors, whose organs are viable because the individual was kept on ventilatory support, and the family decides for organ/tissue donation during that period.
  • Organ/tissue:  Donation of circulatory-death donors as per their will, the organs are retrieved and harvested from the dead body for use for transplant, generally within a few hours after circulatory death (stoppage of the heart). The result of the transplantation of these organs is inferior to those received from the brain-dead.

Transplant Rejection

For any successful tissue transplant without immunological rejection, matching HLA types for MHC genes between the donor and recipient is of paramount importance. The greater the genetic disparity in HLA alleles between donor and recipient, the stronger and more rapid will be the rejection reaction.

• Besides the rejection reaction, a peculiar problem occurring especially in bone marrow transplantation is the graft-versus-host (GVH) reaction.
• In humans, GVH reaction results when immunocompetent cells are transplanted to an immunodeficient recipient for example, Treating severe combined immunodeficiency by bone marrow transplantation.
• The clinical features of GVH reaction include fever, weight loss, anemia, dermatitis, diarrhea, intestinal malabsorption, pneumonia, and hepatosplenomegaly.
• The intensity of the GVH reaction depends upon the extent of genetic disparity between the donor and recipient.

Mechanisms of Transplant Rejection:

• Except for autografts and grafts, an immune response against allografts is inevitable. The development of immunosuppressive drugs has made the survival of allografts in recipients possible.
• Rejection of allograft involves both cell-mediated and humoral immune responses, and accordingly is the type of rejection reaction:

Cell-Mediated Immune Reaction:

Acute cellular transplant rejection occurs in the initial weeks following graft and is majorly due to T cell-mediated cellular immune reactions.

The lymphocytes of the recipient on coming in contact with HLA antigens of the donor are sensitized in case of incompatibility:

• One possible mechanism is that sensitized suppressor T (CD8+) cells (also called cytotoxic lymphocytes) destroy the graft cells directly.
• Alternatively, activated T helper (CD4+) cells secrete pro-inflammatory cytokines which cause inflammatory destruction of the graft.
• T cells may also play a role in chronic graft rejection by their action on vessel walls in the graft, elaborate cytokines that incite inflammation, and promote cellular proliferation.

Humoral Immune Reaction:

Humoral immune reactions by secretion of antibodies against alloantigens in the graft play a role in all types of graft rejections (hyperacute, acute antibody-mediated, and chronic rejection).

The mechanisms are as under:

• Hyperacute rejection reaction: Occurs by the presence of preformed circulating anti-donor antibodies due to pre-sensitization of the recipient before transplantation for example, By blood transfusions, or previous pregnancies.
• Acute antibody-mediated rejection: May occur in graft recipients who are not previously sensitized, but after transplantation, they form antibodies against antigens of class 1 and 2 of donor graft which brings about rejection reaction for example, By inflammation, complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity (ADCC) and antigen-antibody complexes.
• Chronic antibody-mediated graft rejection: May occur after a long delay, often months to a year. It is due to the formation of antibodies in circulation rather than at the graft site and these antibodies often attach to graft vasculature.

Morphology Of Transplant Rejection

As stated above, based on the underlying mechanisms and period, rejection reactions are classified into 3 types:

1. Hyperacute
2. Acute and
3. Chronic.

Hyperacute Rejection:

Hyperacute rejection appears within minutes to hours of placing the transplant and destroys it. It is mediated by preformed circulating humoral antibodies against donor-antigen.

Cross-matching of the donor’s lymphocytes with those of the recipient before transplantation has diminished the frequency of hyperacute rejection.

• Grossly: Hyperacute rejection is recognized by the surgeon soon after the vascular anastomosis of the graft is performed on the recipient’s vessels. The organ becomes swollen, oedematous, hemorrhagic, purple, and cyanotic rather than gaining a pink color.
• Histologically: The characteristics of the Arthus reaction are present. There are numerous neutrophils around dilated and obstructed capillaries which are blocked by fibrin and platelet thrombi. Small segments of the blood vessel wall may become necrotic and there is necrosis of much of the transplanted organ. Small hemorrhages are common.

Acute Rejection:

This usually becomes evident within a few days to a few months of transplantation. Acute graft rejection is more often from cellular rejection but may occur by antibody-mediated rejection reaction too in non-sensitive individuals.

Microscopically: The features of the two forms are as under:

• Acute cellular rejection:
• It is characterized by extensive infiltration in the interstitial of the transplant by lymphocytes (mainly T cells), a few plasma cells, monocytes, and a few polymorphs. There is damage to the blood vessels and there are loci of necrosis in the transplanted tissue.
• Acute humoral rejection: This appears due to poor response to immunosuppressive therapy. It is characterized by acute rejection vasculitis and foci of necrosis in small vessels.
• The mononuclear cell infiltrate is less marked as compared to acute cellular rejection and consists mostly of B lymphocytes.

Chronic Rejection:

Chronic rejection may follow repeated attacks of acute rejection or may develop slowly over months to a year or so. The underlying mechanisms of chronic rejection may be by

• Circulating antibodies
• Secretion of cytokines by T cells, or
• Due to ischemia.

Patients with chronic rejection of renal transplant show progressive deterioration in renal function as seen by rising serum creatinine levels.

• Microscopically: In chronic rejection of transplanted kidneys, the changes are intimal fibrosis, interstitial fibrosis, and tubular atrophy. Renal allografts may develop glomerulonephritis by transmission from the host or rarely may develop de novo glomerulonephritis.

Transplantation:

Tissue transplants are most often allografts and are frequently done for skin, bone marrow, kidney, and liver. HLA matching between donor and recipient is essential before tissue transplantation.

• Graft versus host (GVH) reaction occurs when bone marrow cells are transplanted from an immunocompetent donor to an immunodeficient host.
• Graft rejection of other solid organs is mediated mainly by cell-mediated immune reactions via T cells (direct cytotoxicity by CD8+ cells, and from cytokines by CD4+ cells), and via humoral antibodies. It may be hyperacute, acute, or chronic rejection.
• Hyperacute rejection appears within minutes to hours and is due to the presence of preformed circulating anti-donor antibodies.
• Acute rejection becomes evident within a few days to a few months, and is often from T cell-mediated cellular rejection but can also occur from anti-donor antibody formation.
• Chronic rejection occurs after many months to a year. It may follow repeated attacks of acute rejection or develop slowly from both cytokines from T cells or antibodies in circulation.