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P12P12TheThe

LongLongWaitWait

Team 2Team 2 Abid, Alia, Zoei, Wenny, NithiyaAbid, Alia, Zoei, Wenny, Nithiya

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ObjectivesObjectives

Kidney Problem Causes and Complication (Nithiya) What is organ transplantation?

Laboratory test to determine suitable level of organ transplantation (Abid)

Criteria for considering a suitable donor or recipient

Organs/ tissues that can be transplanted (Zoei)

Four Main Category of Transplant Graft V Host Reaction (wenny)

Post transplantation medication (Alia)

- Pros and Cons of these drugs

- Types of immunosuppressive drugs

What is HLA? (wenny)

Different classes of HLA

PROBLEM STATEMENT (Alia)

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What is organ transplantation?

Is the moving of an organ from one body to

another

Organs that can be transplanted are the heart,kidneys, liver, lungs, pancreas, intestine, and

thymus

Organ donors alive or dead

Transplant region

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Kidney problemsKidney problems

Kidney slows down or stops working

Kidney failure and several complications

Common types of kidney dieases

Chronic kidney failure Acute kidney failure

ESRD

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TreatmentTreatment

Dialysis - is a process for removing waste and

excess water from the blood

Not a one time treatment Kidney transplantation

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Lab test to determine suitable level of organ

transplantation

First test: Blood Type Testing

Second test: Tissue Typing

It is to test out whether the HLA of the donor is compatible with the recipient.

The WBC is accounted for during the tissue typing test.

Third test: Crossmatching Testing of the blood of the recipient to see whether it have a reaction to the donors organ.

If the test is positive, the organ is incompatible. If it is negative, the organ is compatible

Fourth test: Serology:

Blood test conducted for potentially transmitted diseases (HIV, Hepatits)

Recipient's Blood Donors Blood

A A or O

B B or O

O O

AB A, B, AB or O

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Criteria for considering a suitable donor or

recipient

Same blood type

Compatible HLA

Compatible antibodies

Functional organs

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Organs / Tissues that can be

Transplanted Organ Transplantation The moving of an organ from one body to

another or from a donor site on the patient's own body

Organs that can be transplanted Heart, Kidneys, Liver, Lungs,

Pancreas, Intestine, and Thymus

Tissues that can be transplanted Bones, Tendons, Cornea, Skin,

Heart Valves, and Veins

Organ donors Living orBrain-dead

Most tissues, except the corneas, can be preserved and stored for

up to five years

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Four main Types of

Transplantation Autograft- Self transplant- No immune issues from this.

Allograft- Most common type and is transplant of non-identical people

- Immunosuppressants need to be taken to prevent the body from

rejecting this type of transplant

Isograft

- From genetically identical people- Anatomically like allografts, but no immune response

Xenograft

- Transplant from another species

- There will be immune issues and person needs

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Post Transplantation MedicationPost Transplantation Medication

Immunosuppressive drugs or immunosuppressive agents are drugs thatinhibit or prevent activity of the immune system.

They are used in immunosuppressive therapy to:

Prevent the rejection of transplanted organs and tissues.

Treat autoimmune diseases or diseases that are most likely of autoimmuneorigin.

Treat some other non-autoimmune inflammatory diseases.

Groups of Immunosuppressive Drugs:

Glucocorticoids Cytostatics

Antibodies

Drugs acting on immunophilins

Other Drugs

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Disadvantages of these medications

It is able to gain infection easily and the spread of malignantcells.

There are also side effects:

- Hypertension- Dyslipidemia

- Hyperglycemia

- Peptic ulcers

- Liver and kidney injury

It also interacts with other medicines and affect theirmetabolism and actions.

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HLA

Proteins present on the surface of all cells onthe human body.

Resides on chromosome number 6

Recognize foreign cells.

MHC Class I HLA-A, HLA-B, HLA-C

MHC Class II - HLA-DP, HLA-DQ, HLA-DR antigens

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MHC Class I

Present peptides from inside the cell.

Peptides are produced from digested proteinsthat are broken down in the proteasomes.

MHC Class II

Present antigens from outside of the cell to T-

lymphocytes. Stimulate T-helper cells stimulate antibody-

producing B-cells

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Graft V Host Reaction

An immunologically competent graft is transplantedinto an immunologically suppressed recipient (host)

Criteria: An immunocompetent graft is administered, with

viable and functional immune cells.

The recipient is immunologically disparate -

histoincompatible. The recipient is immunocompromised and therefore

cannot destroy or inactivate the transplanted cells.

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Problem

Statement

The every cadavers mentioned in the problem statement should refer to allograft.

Allograft are transplants that are performed between 2 genetically non-identical

members of the same species. Most human tissues/organ transplant are allograft.

Due to the genetic difference between the donor & recipient, the recipients

immune system will detect the organ as foreign object and will try to destroy it

which leads to transplant rejection.

Transplant rejection occurs when a transplanted organ or tissue is not accepted by

the body of the transplant recipient.

When possible, transplant rejection can be reduced through serotyping to

determine the most appropriate donor-recipient match and through the use of

immunosuppressant drugs.

Mr. Teos doctor told him that not every cadaver wasMr. Teos doctor told him that not every cadaver was

suitable for him and transplantation of a nonsuitable for him and transplantation of a non--

compatible kidney will put him in grave danger.compatible kidney will put him in grave danger.

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Resources

http://en.wikipedia.org/wiki/Transplant_rejection http://en.wikipedia.org/wiki/Human_leukocyte_antigen

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Major Histocompatibility Complex

(MHC)

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Major Histocompatibility Complex (MHC)

* The MHC is a closely linked complex of genes that govern production ofthe major histocompatibility

* In humans, MHC resides on the short arm of chromosome 6

* 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

* HLA genes are very diverse (polymorphic)

i.e. there are many alleles of the class I and II genes

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Major Histocompatibility Complex (MHC)

* Between the class I and class II gene loci, there is a third locus (Class

III)

* This locus contains genes encoding tumor necrosis factor,

lymphotoxin and two complement components (C2 and C4)

* Class III antigens do not participate in MHC restriction or graft

rejection

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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

* HLA-A contains 24 different antigenic specificities,

HLA-B contains 52 and HLA-C contains 11

* Class I MHC antigens are involved ofMHC restriction of cell

mediated cytotoxicity

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MHC Restriction

* 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-cellswhich then kill these cells

* In other words;

T-cells are only activated when they recognize both antigen andclass I MHC molecules in association

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MHC Class II Antigens

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 skinand activated T cells

HLA-DP contain 6 different antigenic specificities, HLA-DQ

contains 9 and HL

A-DR contains 20

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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

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Class I MHC and Class II MHC

MHC Class IMHC Class I MHC Class IIMHC Class II

NomenclatureNomenclature HLAHLA--A, HLAA, HLA--B, HLAB, HLA--CC HLAHLA--DP, HLADP, HLA--DQ,DQ,HLAHLA--DRDR

Found onFound on

All nucleated somaticAll nucleated somatic

cellscells

Macrophages, BMacrophages, B--cells,cells,

Dentritic cells,Dentritic cells,langerhans cells of skinlangerhans cells of skin

and activated T cellsand activated T cells

Recognized byRecognized by CD8 TC cellsCD8 TC cells CD4 TH cellsCD4 TH cells

FunctionsFunctions Presentation of Ag toPresentation of Ag toTCTC cells leading tocells leading to

elimination of tumor orelimination of tumor orinfected host cellinfected host cell

Presentation of Ag toPresentation of Ag toTHTH cells whichcells which secretesecrete

cytokinescytokines

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Transplantation

andGraft Rejection

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Types of grafts

1) Autografts :

The transfer of an individuals own tissues

from place to place

e.g. Skin grafts (regularly accepted)

2) Isografts :

Transfer oftissues between genetically

identical persons

e.g. Identical twins ( accepted permanently)

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Types of grafts

3) Allografts (homograft):

- Transfer of a graft between genetically different

members of same species

e.g from one human to another- Rejection occur if donor and recipient are not matched

4) Xenograft (heterograft):

- Transfer of tissues between different species

- Always rejected

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Mechanism Of Graft Rejection

1) Both TH and TC are activated- TC cells destroy graft cells by direct contact

TH cells secrete cytokines that attract and activate macrophages,NK cells and polymorphs leading to cellular infiltration anddestruction of graft (Type IV)

- B cells recognize foreign antigens on the graft and produceantibodies which bind to graft cells and

. Activate complement causing cell lysis

. Enhance phagocytosis, i.e. opsonization (Type II)

. Lead to ADCC by macrophages, NK,PML

- Immune complex deposition on the vessel walls induce plateletsaggregation and microthrombi leading to ischemia and necrosis

of graft (Type II)

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Types Of Graft Rejection

!) Hyperacute rejection:

- It occurs hours after transplantation

- In individual with preformed antibodies either due to - blood groupsincompatibility or previous sensitization

by blood transfusion, previous transplantation

2) Acute Rejection:

- It occurs 10 to 30 days after transplantation

- It is mainly T-cell mediated

3) Chronic or late rejection:

- It occurs over a period ofmonths or years

- It may be cell mediated, antibody mediated or both

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Graft Versus Host (GVH) Reaction

* An immunologically competent graft is transplanted into an

immunologically suppressed recipient (host)

* The grafted cells survive and react against the host cells

i.e instead of reaction of host against the graft,

the reverse occurs

* GVH reaction is characterized by fever, pancytopenia, weight loss, rash ,

diarrhea, hepatsplenomegaly and death