Organ Transplantation

Clinical immunology L-8

Organ Transplantation
Transplantation refers to the act of transferring cells, tissues, or organs from one site to another.
Or is the process of taking cells, tissues, or organs, called a graft, from one individual and placing them into a different individual.

individual who provides the graft:

donor

individual who receive the graft:

recipient

Transplanted organs\tissues

-liver
-kidney
-pancreas
-heart
-lung
-intestine
-face
-bone marrow
-cornea


Types of donor
_living
The donor remains a live and donates a renewable tissue, cell, or fluid( e.g. blood, skin), or donates an organ or part of an organ in which the remaining organ can regenerate or take on the workload of the rest of the organ (primarily single kidney donation, partial donation of the liver)
--deceased(formerly cadaveric)
Are donors who have been declared brain-dead and whose organs are kept viable by ventilators or other mechanical mechanisms until they can be excised for transplantation.

Types of transplant

*autograft is self-tissue transferred from one body site to another in the same individual
*isograft is tissue transferred between genetically identical individuals
*allograft is tissue transferred between genetically different members of the same species
*xenograft is tissue transferred between different species

Pre-transplantation evaluation

-blood type ( A,B, AB and O)
-human leukocyte antigens( HLA) tissue typing
-serology; for HIV, CMV and hepatitis
- cardiopulmonary, cancer screening

HLA tissue typing

- matching of stem cell donor to a recipient is determined by comparing their tissue types
- an individual’s HLA type is present on nearly all tissues in the body
- the white cells from a blood sample are a convenient source of ‘tissue’ that the laboratory can use to determine an individual’s HLA type.


Why is HLA typing important?
-because the degree of HLA compatibility between donor and recipient will influence the outcome of transplant.
-the function of the immune system is to fight against foreign particles such as bacteria and viruses.
.

A stem cell transplant from an HLA mismatched donor can result in recipient's immune system recognizing the transplanted cells as( non selfing) and attacking the cells as it would for bacteria or viruses. This can lead to rejection of the transplanted stem cells

Likewise cells from the donor’s immune system which are introduced along with the transplanted stem cells ‘graft’ can also recognize HLA mismatches and attack vital organs of the recipient ‘s body ‘host’. This is also called graft versus host disease ( GvHD).

-the more compatible the donor- recipient match, the less likely it is that rejection or severe GvHD will occur.

How is HLA typing performed?

- a 20-30 ml blood sample is required to perform HLA typing. The white cells are isolated from the blood and typing is performed by two different methods:
1- serological testing: where the white cells are used
2- DNA testing : where DNA extracted from the white cells is used.
Preliminary tissue typing takes about 2 weeks. Further high resolution (more detailed) tissue typing performed on the patient and any potentially matched donor samples may take another 2-4 weeks.

Searching for a related donor

- an HLA type consist of two main groups:
Class I antigens ( HLA-A,-B, -C) and class II antigens ( HLA- DR, -DQ, DP)
- there are six antigens considered most important for determing compatibility: two A antigens, and two DR antigens, and two B antigens.
-we inherit a set (or haplotype) of HLA-A, B, and DR antigens from each parent.


HLA antigens corresponding to MHC class I ( A,B &C) present peptides from inside the cell (including viral peptide if present)
- HLA antigens corresponding to MHC class II (DP,DQ & DR) present antigens from out side of the cell to T –lymphocytes.
-HLA typing of potential donors and a recipient can be accomplished with a microcytotoxisity test.

Immunology of transplant rejection

Component of the immune system involved in graft rejection
1- antigen presenting cells:
-dendritic cells
- macrophage
-activated B cells
2- B cells and antibodies
3- T cells
4- other cells
- natural killer cells
- monocytes

The immunology of allogeneic transplantation

- recognition of transplanted cells that are self or foreign is determined by polymorphic genes (MHC) that are inherited from both parents and are expressed co-dominantly.
- alloantigens elicit both cell- mediated and humeral immune responses.

Recognition of alloantigens

Direct presentation
- recognition of an intact MHC molecule displayed by donor APC in the graft
-basically, self MHC molecule recognizes the structure of intact allogeneic MHC molecule
- involves both CD8 and CD4 T cells


Indirect presentation
-donor MHC is processed& presented by recipient APC
- basically, donor MHC molecule is handled like any other foreign antigen
- involve only CD4 T cells
- antigen presentation by class II MHC molecules.

Role of CD4 and CD8 T cells

-CD4 differentiate into cytokine producing effector cells
*damage graft by reactions
-CD8 cells activated by direct pathway kill nucleated cells in the graft

Effector mechanisms of allograft rejection

-hyperacute rejection
-acute rejection
- chronic rejection

hyperacute rejection

-characterized by thrombotic occlusion of the graft
-begins within minutes or hours after hosts blood vessels are anastomosed to graft vessels
-pre- existing antibodies in the host circulation bind to donor endothelial antigens
-activates complement cascade.



acute rejection
-vascular and parenchymal injury mediated by T cells and antibodies that usually begin after the first week of transplantation
-incidence is high (30%) for the first 90 days.

chronic rejection

-occurs in most solid organ transplant
*heart
* kidney
* lung
*liver
- characterized by fibrosis and vascular abnormalities with loss of graft function over a prolonged period.

TRANSPLANTATION & GRAFT REJECTION

Transplantation provides the opportunity for definitive treatment of end organ disease.

The complications after transplantation depend on:

1-the organ transplanted
2-the genetic disparity between recipient& donor
3-the primary disease &
4-drug therapy used


The major complications are GRAFT REJECTION& INFECTION.

The difference between the recipient & donor HLA proteins, the nature of transplanted tissue& the immune status of the recipient determine the nature & severity of rejection.

Histological analysis of rejected organs shows a range of immunological processes in action. With modern tissue-matching approaches, hyper acute rejection is rare & acute rejection can usually be prevented or treated with immunosuppression.

As a consequence of the vigorous immunosuppression required to avoid allograft rejection, secondary immunodeficiency often arises in graft recipients, manifesting as infections & malignancies.

Cytomegalovirus is particularly common, along with herpes viruses, fungal organisms(aspergillus & Nocardia spp., cryptococcal infection), mycobacteria& parasites (pneumocystis, toxoplasma spp.).

The most common cancers seen after organ transplantations are lymphoma, skin cancers & Kaposi's sarcoma.

Liver transplantation

The outcome fallowing liver transplantation has improved over the past decades, but the number of the procedures is limited by cadaver donor availability. This limitation had partially solved by development of living donor liver transplantation.


The main complication of liver transplantation is related to disease recurrence in the liver graft.
10% of LT is performed for acute liver failure
6% for metabolic diseases
70% for liver cirrhosis
11% for hepatocellular carcinoma


Contraindications to Liver Transplantation
a-sepsis
b-extra hepatic cancers
c-cardio respiratory dysfunction
d-active alcohol intake.

patients candidate for liver transplantation are ABO &size matched but not HLA –matched with donor.
Less immunosuppression is noted following LT than with kidney & heart –lung transplantation.

Acute rejection: occurs in up to 60% of cases, usually within first 6 weeks after transplantation & responds to 3 days course of high dose of methylprednisolone.
Chronic vascular rejection is rare &occurs in only 5% of cases.

Graft versus host disease(GVHD)

This type of rejection is due to cytotoxic activity of donor T-lymphocytes in patients with bone marrow transplantation which become sensitized to there new host regarding it as a foreign.

Acute GVHD: occurs in first 100 days fallowing transplantation in 1/3 of patients. It can affect skin causing rashes, liver causing jaundice & the gut causing diarrhea.

Prevention includes HLA matching of the donor & immunosuppressive drugs including methotrexate , cyclosporine & anti-thymocyte globulin. The more sever forms prove fatal in spite of high dose steroids.

Chronic GVHD

This may fallow acute GVHD or arise independently & occurs later than acute GVHD.



It often presents similar to connective tissue disease, although in mild forms, skin rash is the only manifestation.

Chronic GVHD is treated with corticosteroids &prolonged use of immunosuppressive agents like cyclosporine.

Graft versus leukemia effect often fallow chronic GVHD & this is beneficial in terms of reduction of relapse rate fallowing bone marrow transplantation.