Organ Transplantation, Immunology And Rejection

OS 214: Excretory System

Dr. Dennis Serrano

Exam #2

Organ Transplantation, Immunology and Rejection

OUTLINE I. Intoduction to Organ Transplantation II. Intoduction to Transplant Immunology and Rejection PART 1. Six organs maybe transplanted: • Kidney • Heart • Pancreas • Lung • Liver • Small intestine

Development of Organ Transplantation

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Replacement of tissue with artificial parts. Dates back several hundred years ago Chinese drawing: heart being taken or replaced Cosmos and Damien (Patron Saints of Transplantation) with angels in the background: replacing a leg o 1950s: First successful transplant (kidney) on identical twins. Sir then showed a picture of a healthy kidney with the ureter vein and artery resting on the iliac area. Sabi niya, hindi tinatanggal yung lumang kidneys pag nagtratransplant, dinadagdagan yung kidney, nilalagay ung bago sa iliac area. Thus, 3 na yung kidney nung pasyente :p Tapos picture naman ng kidney na nireject, nagging kulay violet na at ayon sa 2011, thrombosed na daw. Organs are harvested en bloc from cadaver donors. o o

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Rules of Tissue Transfer Blood Type Donor Blood Type Recipient Blood Type O* non-O RhRh+ Rh+ RhA non-A B non-B AB** non-AB *Universal Donor; **Universal Recipient

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Gene found in chromosome 6 that is important in transplantation.

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There are 6 loci, but for organ transplantation, only HLA-A, HLA-B, and HLA-DR matter. (we have 2 of each, therefore, 6 ang minamatch) Blood type must match first before proceeding to HLA matching. The number of matches/mismatches predict the probability of transplant success. o Best: 0 mismatch (6 match) o Worst: 6 mismatch (0 match) However, pwede pa rin magtransplant kahit na 6 mismatch, mas-iiimmunosuppress lang.

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HLA-DR is most predictive of rejection (kung nagmatch ang isang HLA-DR sa isang donor, kahit

March 17, 2009 | Tuesday

Cross-matching

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A test for identification of antibody in the serum of potential recipients which reacts directly with the lymphocytes or other cells of a potential donor • A positive crossmatch is an absolute contraindication to transplantation Other Considerations • Patient’s immune status (no transplants for AIDS patients) • Co-morbidities What Leads to Rejection • Recognition of foreign antigen (donor organ) • Activation and proliferation of antigen specific lymphocyte • Damage to donor organ by antibodies. What to do to prevent rejection

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1960s: whole body irradiation (not done today) o

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Prevents acute rejection, but not delayed. Patients body eventually recovers and manufactures antibodies.

Drugs – immunosuppressants; anti-thymus globulins o

o o

Human T lymphocytes in thymus injected into the horse / rabbit Antibodies against human T lymphocytes are developed Antibodies are injected to the recipient, where T lymphocytes of the recipient will be killed

Organ Donation • In some countries, brain dead = organ donor.

• Safety safe safe safe dangerous dangerous dangerous

Human Leukocyte Antigen (HLA)

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meron pang donor na nagmatch ung HLA-A at HLAB, un pa ring may match ng HLA-DR ang pipiliin).

Here in the Philippines, there are donor cards. (Back of driver’s license, etc)

Brain Death Criteria • Deep Coma • No breathing • No movement (except DTRs) • No brainstem reflexes o No papillary light reflex o No blinking o No eye movement o No grimacing o No gagging or coughing

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Body temp > 32.20C

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A condition that can cause brain death must be established No depressant drugs in blood/ urine

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*Bedside diagnosis; transplant surgeon cannot proclaim brain death.

Criteria of Organ Donation Compatibility*

Organ

Age Limit

ABO

HLA

Cornea Kidney Pancreas

65 65-70 15-50

+ +

+ +

Maximal tissue Crossmatch ischemia 72 hrs. + 72 hrs. Page 1 of + 24 hrs.

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Cielo  Co  Collantes  Concepcion

OS 214: Excretory System

Dr. Dennis Serrano

Organ Transplantation, Immunology and Rejection

Liver Lung Heart

65-75 50 55-60

+/+ +

-

+/+/-

18-24 hrs. 6 hrs. 6 hrs.

Exam #2

cascade of immune reactions. Most immunosuppressive drugs used to prevent rejection target the Th.

*+, criterion; -, not a criterion PART 2.

Classification of Rejection 1. Hyperacute

Histocompatibility

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Mutual tolerance between tissues that allows them to be grafted effectively.

Pre-transplant Histocompatibility Testing Blood Typing • ABO Blood Group Tissue Typing • Major Histocompatibility Complex (MHC) Antigens • Glycoproteins on cell membranes • Encoded by MHC genes in short arm of Chr 6 • 2 Classes: o Class I: HLA-A, HLA-B, HLA-C o Class II: HLA-DP, HLA-DR, HLA-DQ Tissue Cross-matching

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Detects circulating PREFORMED cytotoxic antibodies

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Keyword here is PREFORMED o from previous blood transfusion o pregnancy (fetus is considered a foreign body) o from previous transplant (these patients are called “sensitized people”; their immune systems have already been alerted before)

Indirect Allorecognition Recipient APC

Direct Allorecognition Donor APC

Self-MHC Class II Ag + Allopeptide + Co-stimulatory 2nd Signal

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In patients with pre-formed cytotoxic Ab

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Within minutes to hours after transplant

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In recent years, this has been prevented through pre-transplant tissue cross-matching Accelerated

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3.

Within days to weeks (~2-3 days)

• Flu-like symptoms • Humoral and cellular components • Doesn’t respond to anti-rejection treatment Acute • With flu-like symptoms as well

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Myalgia, malaise, fever, decrease in urine output, high creatinine, tender graft, HPN • Manifests weeks to months post-transplant • There is graft swelling (local inflammation) • Tx: increase immunosuppression Chronic

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Gradual decline in kidney function

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There is interstitial fibrosis Continuous bombardment with focal inflammatory reactions slowly scars kidney tissue

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Manifests years after sugery Cannot be prevented (Kaya may lifespan ang

AlloMHC Class II Ag + Co-stimulatory 2nd Signal Th

(IL2, IL 3-6. calcineurin, IF, NFAT) pCTL

B-Cell

+Alloantigen

+Alloantigen

CTL

Plasma Cell

Cytotoxicity

Alloantibody

Complement Mediated Damage

Macrophage NK Cells Delayed Type Hypersensitivity

ADCC

Figure 1. Antigen-Presenting Cells (APC), whether from the recipient or from the donor, are needed to activate Th release of cytokines, which would in turn, activate a

March 17, 2009 | Tuesday

organ transplants. Pag bata ka natransplant, most probably, you will need a second.) Figure 2. Immunosuppressants and their targets

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