TRANSPLANTATION

MATEEN IRFANSHA .

TRANSPLANTATION:- The transfer (an organ or tissue) from one part of the body to another or from one person (the donor) to another (the recipient). Most common transplantation is blood transfusion.

The heart, kidneys, liver, lungs, pancreas, intestine, and thymus.

The kidneys are the most commonly transplanted organs, followed closely by the liver and then the heart.  

•TISSUES THAT CAN BETRANSPLANTED ARE:- Tissues include bones, tendons (both referred to as musculoskeletal grafts), cornea, skin, heart valves, and veins .The cornea and musculoskeletal grafts are the most commonly transplanted tissues.

•ORGANS THAT CAN BE TRANSPLANTED ARE :-

Classification of transplantation:-•  Autotransplantation (Autografts):-– Grafts transplanted from one part of the body to another in

the same individual –   Sometimes this is done with surplus tissue, or tissue that

can regenerate– E.g :- Skin grafts, Bone grafts.

• Isograft (Syngeneic grafts):-– Grafts transplanted between two genetically identical

individuals of the same species.– Isografts are differentiated from other types of transplants

because while they are anatomically identical to allografts, they do not trigger an immune response..

• Allotransplantation (Allogeneic grafts ) :-

- Grafts transplanted between two genetically different individuals of the same species  ( living or cadaveric sources)

- Most human tissue and organ transplants are allografts. Due to the genetic difference between the organ and the recipient, the recipient's immune system will identify the organ as foreign and attempt to destroy it, causing  transplant rejection.

- E.g :- Kindney , Heart & Liver transplantation

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•Xenotransplantation(Xenografts):--Grafts transplanted between individuals of different species.

-A major barrier to xenogeneic transplantation is the presence of natural antibodies that cause hyperacute rejection.

-E.g:-porcine heart valve transplantation & fish to non-human primate transplant of islet

•Split transplants :- -Sometimes a deceased-donor organ, usually a liver, may be divided between two recipients, especially an adult and a child. This is not usually a preferred option because the transplantation of a whole organ is more successful.

What is graft rejection?The immunologic destruction of transplanted organs or tissues. The rejection may be based on both cell-mediated and antibody-mediated immunity against cells of the graft by a histoincompatible recipient.

• Grafts rejection is a kind of specific immune response.

• Grafts rejection:-– First set rejection:-when skin is grafted between unrelated

or allogeneicindividuals (an allograft), the graft is initially accepted but is then rejected about 10–13 days after grafting (Fig.).This response is called a first-set rejection 

•Allograft Rejection:-

-Second set rejection:- When a recipient that has previously rejected a graft is regrafted with skin from the same donor, the second graft is rejected more rapidly (6–8 days) in a second-set rejection and the accelerated response is MHC-specific.

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•Components of the Immune system involved in graft Rejection :

1) Antigen presenting cells – Dendritic cellsMacrophagesActivated B Cells2) B cells and antibodies – Preformed antibodiesNatural antibodiesInduced antibodies3) T cells4) Other cells – Natural killer cellsMonocytes/Macrophages

Classification of Allograft Rejection:-1. Host versus graft reaction (HVGR)

Conventional organ transplantation2. Graft versus host reaction (GVHR)

Bone marrow transplantationImmune cells transplantation

TYPES OF ALLOGRAFT REJECTION:- 1) Hyperacute rejection:- .Occurrence time:-

Occurs within minutes to hours after host blood vessels are anastomosed to graft vessels. .Pathology :- Thrombotic occlusion of the graft vasculature

Ischemia, denaturation, necrosis

1.Host versus graft reaction (HVGR)

Mechanisms:-Preformed antibodies

1. Antibody against ABO blood type antigen2. Antibody against VEC ( vascular endothelial cell)

antigen 3. HLA antigen

2) Acute Rejection:-

Occurrence time :-Occurs within days to 2 weeks after transplantation, 80-90% of cases occur within 1 month.

Pathology :-• Acute humoral rejection:-

Acute vasculitis manifested mainly by endothelial cell damage

• Acute cellular rejection:-Parenchymal cell necrosis along with infiltration of lymphocytes and MΦ

Mechanisms Vasculitis:-

IgG antibodies against alloantigens on endothelial cell CDC

Parenchymal cell damage:-• Delayed hypersensitivity mediated by CD4+Th1• Killing of graft cells by CD8+Tc

3) Chronic or late rejection:-

Occurrence time:-Develops months or years after acute rejection reactions have subsided

Mechanisms -Not clear-Extension and results of cell necrosis in acute rejection-Chronic inflammation mediated by CD4+T cell/MΦOrgan degeneration induced by non immune factors

Pathology:-Fibrosis and vascular abnormalities with loss of graft function

Transplantation antigens:-

•Major histocompatibility antigens :- (MHC molecules, Main antigens of grafts rejection ). - Cause fast and strong rejection -Difference of HLA types is the main cause of human grafts rejection.

•Minor histocompatibility antigens:- (Also cause grafts rejection, but slow and weak)

•Other alloantigens:- (Human ABO blood group antigens).

Major Histocompatibility Complex (MHC)

•MHC Class I:-•Three genes (HLA-A, HLA-B, HLA-C) code for the class- I MHC proteins.

• Several HLA-D loci determine the class II MHC proteins i.e. DP, DQ and DR

In humans, MHC resides on the arm of chromosome 6

MHC Class I Antigens:-•Class I MHC antigens are : HLA-A, HLA-B and HLA-C

• These antigens are glycoproteins found on surfaces of all nucleotide human cells and on platelets

• Class I MHC antigens are involved of MHC restriction of cell mediated cytotoxicity

• Endogenously processed cytosolic peptides in virus infected cells or tumor cells are transported to the surface of the cells

• They bind to MHC I molecules to be recognized by cytotoxic T-cells which then kill these cells

•MHC Class II:-

Major Histocompatibility Complex (MHC)

In humans, MHC resides on the arm of chromosome 6

•MHC Class I:-•Three genes (HLA-A, HLA-B, HLA-C) code for the class- I MHC proteins.

• Several HLA-D loci determine the class II MHC proteins i.e. DP, DQ and DR

•MHC Class II:-

•Class II antigens are: HLA-DP, HLA-DQ, HLA-DR antigens

•These antigens are glycoproteins found on the surface of macrophages, B-cells, Dentritic cells, langerhans cells of skin and activated T cells

MHC Class II Antigens

• Helper T-cells recognize antigens on antigen-presenting cells only when the antigens are presented on the surface of cells in association with class II MHC

• Class II antigens react with the CD4 molecule on the helper T-cells which secrete cytokines

Class I MHC and Class II MHC MHC Class I MHC Class II

Nomenclature HLA-A, HLA-B, HLA-C HLA-DP, HLA-DQ, HLA-DR

Found on All nucleated somatic cells

Macrophages, B-cells, Dentritic cells,

langerhans cells of skin and activated T cells

Recognized by CD8 TC cells CD4 TH cells

Functions Presentation of Ag to TC cells leading to

elimination of tumor or infected host cell

Presentation of Ag to TH cells which secrete

cytokines

Mechanism of graft rejection :-1) Cell-mediated Immunity.

2) Humoral immunity.

1) Cell-mediated Immunity :-• Recipient's T cell-mediated cellular immune response against

alloantigens on grafts.• T cells of the recipient recognize the allogeneic MHC

molecules :• Direct Recognition &• Indirect Recognition

•Direct recognition :-•Recognitio of an intact MHC molecule displayed by donor APC in the graft•Involves both CD8+ and CD4+ T cells. n

•Indirect recognition :-• Donor MHC is processed and presented by recipient APC.•Basically, donor MHC molecule is handled like any other foreign Ag.• Involve only CD4+ T cells.•Antigen presentation by class II MHC molecules.

Direct Recognition

Indirect Recognition

Allogeneic MHC molecule

Intact allogeneic MHC molecule

Peptide of allogeneic MHC molecule

APCs Recipient APCs are not necessary

Recipient APCs

Activated T cells CD4 ＋T cells and/or CD8 ＋T cells

CD4 ＋T cells and/or CD8 ＋T cells

Roles in rejection Acute rejection Chronic rejection

Degree of rejection Vigorous Weak

Difference between Direct Recognition and Indirect Recognition

2) Humoral immunity:- – Ab’s produced against donor Ag can also mediate rejection

through two forms:

I. Hyperacute rejection:• Immediate rejection soon after transplantation.• Occurs when preformed antidonor Ab’s are present in

the circulation of the recipient.

II. Anti-HLA humoral Ab’s • It develops concurrently with T-cell mediated rejection.• Seen in recipients not previously sensitized to

transplantation antigens, exposure to the class I and class II HLA antigens of the donor may evoke antibodies.

• The initial target of these antibodies in rejection appears to be the graft vasculature.

•Caused by the reaction of grafted mature T-cells in the marrow inoculum with alloantigens of the host.

•Acute GVHD:-

Characterized by epithelial cell death in the skin, GI tract, and liver.

•Chronic GVHD:-

Characterized by atrophy and fibrosis of one or more of these same target organs as well as the lungs.

Graft vs. Host Disease:-

Immunosuppressive Agents:-Immunosuppression can be brought about by 3 different ways :-

1)Surgical ablation.2)Total Lymphoid Irradiation.3)Immunosuppressive drugs.

Immunosuppressive Drugs:-

Three main immunosuppressant drugs 1) Cyclosporins:- act by inhibiting T-cell activation, thus preventing T-cells from attacking the transplanted organ. 2) Azathioprines:- disrupt the synthesis of DNA and RNA and cell division.

Q.HOW TO PREVENT GRAFT REJECTION?

•Side-effect:-• immunodeficiency, because the majority of them act non-selectively, resulting in increased susceptibility to infections and •Decreased cancer immunosurveillance.• There are also other side-effects, such as hypertension, dyslipidemia, hyperglycemia, peptic ulcers, lipodystrophy, moon face, liver and kidney injury.

3) Glucocorticoids:-•(Glucocorticoids suppress the cell-mediated immunity. They act by inhibiting genes that code for the cytokines Interleukin 1 (IL-1), IL-2,3,4,5,6,8, and TNF-γ,d most important of which is IL-2. Smaller cytokine productn reduces the T cell proliferatn.

•Glucocorticoids also suppress the humoral immunity, causing B cells to express smaller amounts of IL-2 and IL-2 receptors. This diminishes both B cell clone expansion and antibody synthesis.

PRIMARY goal in organ transplantation:-

•The prevention/effective treatment of infection, d most common life-threatening complication of long-term immunosuppressive therapy.

• immunosuppression-induced impairment of the inflammatory response,which attenuates d sign & symptoms of invasive infection.

•Avoid the adverse effects of the antimicrobial drugs used for prophylaxis and therapy, which result both from the duration of therapy required and from interactions with the immunosuppressive drugs

•Aim is to delineate the principles guiding infectious disease practice in transplantation, emphasizing the prevention and early recognition of infection and the avoidance of common drug-related toxic effects.

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