Transplant Immunology

WHY TRANSPLANT TISSUES OR ORGANS?

Replace dysfunctional/nonfunctional tissue or organs ----------------------------------------------------------------------------- - High technology medicine Specialized healthcare professionals Specialized facilities Specialized support Pathology Radiology - Life saving - Very Expensive ------------------------------------------------------------------------------

DEFINITIONS OF TYPES OF TRANSPLANTS:

--------------------------------------------------------------------- Classification scheme: depends upon: - the species of donor and recipient - same or different?

- genetic similarity of donor & recipient ( assuming both are form the same species ) - identical versus - non-identical ----------------------------------------------------------------------

NOMENCLATURE: Donor (graft) & Recipient (host) Same Genetically Type of

IMPORTANT!

Species Identical transplant / tissue ----------------------------------------------------------------------------- Self-> Self Yes Yes Autologous graft Autograft T win A -> B* Yes Yes Isogeneic graft (syngeneic) Isograft (syngeneic graft) Person A --> B Yes No Allogeneic graft Allograft ** Species A --> B No No Xenogeneic graft Xenograft * ----------------------------------------------------------------------------- Also applies to individuals of an inbred strain (e.g., inbred mice) ** Most common type of transplant in humans

IMPORTANT!

WHAT ARE THE RULES OF TRANSPLANTATION?

Type of Graft Isograft Graft fate without immunosuppression of the recipient (host) --------------------------------------------------------- Autograft Accepted Accepted Allograft Xenograft Rejected* Rejected* ----------------------------------------------------------

* Graft (donor) and Host (recipient) are antigenically dissimilar

Tissue

Autograft

t

Twin “A” TWIN “B” Tissue

Isograft (syngeneic graft)

Tissue

Allogeneic graft (allograft)

Tissue

Xenograft

CLASSIFICATION BY GRAFT LOCATION

Orthograft: transplanted organ is placed in the normal organ location (heart) Heterotopic: transplanted organ is placed in an unnatural location (kidney in pelvis)

WHAT ARE THE TRANSPLANTATION ANTIGENS?

IMPORTANT!

Transplantation Relative Antigens Polymorphism ----------------------------------------------------------------------------- 1) ABO Limited 2) Major histocompatibility complex (MHC)*

Very high

3) Minor histocompatibility antigens(non-MHC antigens) Limited 4) Xenoantigens

Extremely high

----------------------------------------------------------------------------- * Human MHC = HLA Complex, class I and class II MHC

HOW DOES THE RECIPIENT RECOGNIZE THE DONOR AS FOREIGN?

-------------------------------------------------------------------------- H o s t

(Recipient) TCR and B cell receptors

recognize

d o n o r

(graft) antigens as

f o r e i g n -------------------------------------------------------------------------- IMPORTANT

CONCEPT:

----------------------------------------------------------------------------- - the greater the difference in peptide sequences between graft and recipient - the stronger the immune response to the graft ( donor ) ------------------------------------------------------------------------------

HOW CAN FOREIGN CLASS II MHC PRESENT PEPTIDES TO HOST TCRs?

Classification of the phases of tissue rejection Minutes- Hours Days Weeks Months Years Hyper acute Acute Subacute Chronic

Pre-existing immunity to graft antigens Yes No Antibody CMI CMI Antibody + CMI Hyper acute Minutes- Hours Acute Subacute Days Weeks Months Chronic Years

Phase T ime frame Mechanism

Type of Donor - Recipient Mismatch ------------------------------------------------------------------------------

Hyperacute

Minutes -hours

Pre-existing antibodies

anti-ABO, anti-MHC Acute vasc ular ABO MHC obstruction (2 0 set rejection) ------------------------------------------------------------------------------

Type of

Phase T ime frame Mechanism

Donor - Recipient Mismatch ------------------------------------------------------------------------------

Acute*

Days Reactivation of sensitized T cells; 2 nd set rejection Class I or II MHC; minor histo compatibility ----------------------------------------------------------------------------- * some sources refer to this as “accelerated ”

1 0 activation “1 st set rejection”

Type of

Phase Chronic T ime frame

Mismatch ----------------------------------------------------------------------------- Months -Years

Mechanism

Cell-mediated and Ab mediated; Immune Donor - Recipient Class I MHC, Minor histocompati bility complexes* ----------------------------------------------------------------------------- * initial first set rejection evolves into a second set rejection

TIME TO TISSUE REJECTION IN MICE ------------------------------------------------------------------------- Skin graft in mice strain A --> Immune strain B response First set rejection 11 - 15 days Primary Second set rejection 6 - 8 days Secondary ---------------------------------------------------------------------------

IMPORTANT

First Kidney Transplant Surgery: 1950

Transplantation

From Kidney to Stem cell

History of Transplantation in Iran

1 st kidney transplantation in 1967 in Shiraz Dr. Sanadi Zadeh

1985

2 transplantation teams were organized and started to work actively 274 kidney transplant in 2 years

L.R.D L.U.R.D. cadaveric

1988

• L.U.R.D program organized and managed successfully • Number of transplant teams grow to < 20

• To the end of 2002 => 14888 kidney transplant • Today => 1500 kidney transplant/yr in Iran

THE NUMBER OF RENAL TRANSPLANTS PERFORMED IN IRAN FROM 1984 - 2002 1800 1650 1681 1600 1400 Number of Txs 1422 1169 1184 1186 1200 1000 800 600 453 500 583 687 813 755 853 827 400 200 98 158 245 6 18 0 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 2000 2001 2002

SOURCES OF KIDNEY DONATION IN IRAN ; 1984 - 2002

LURD 79% (N=11 292 ) LRD 19.2% (N=2746) CAD 1.8% (N=250)

PATIENT AND GRAFT SURVIVAL RATE IN LIVING RELATED (LRD) AND LIVING UNRELATED (LURD) RENAL TRANSPLANTATION

In Hashemi Nejad Hospital , Tehran

% 100 90 80 70 60 50 40 30 20 10 0 LRD (N=469) LURD (N=881) Patient survival Graft survival P<0.05

1 2 3 4 5 6 Years Post Transplant 7 8 9 10

GRAFT SURVIVAL RATES IN HLA IDENTICAL, ONE HLA HAPLOTYPE MATCH AND LIVING UNRELATED RENAL TRANSPLANT

In Hashemi Nejad Hospital , Tehran

%

100 90 80 70 60 50 40 30 20 10 0 HLA Identical (n=141) One HLA Haplo (n=307) Living Unrelated (n=881) 1 2 3 4 5 6 7 Years Post Transplant 8

P<0.001

P=0.35

9 10

Other Organ transplants

Bone Marrow, Liver & Heart

1991

1 ST BMT in Shariati Hospital (Dr. Ghavamzadeh et al

1991-2006

Total of 1468 BMT Allogenic 1044 Autologous 324

New Topics

Human Stem cell Repertoire

What are stem cells?

• A stem cell is a cell whose job in the body is not yet determined • Every single cell in the body stems from this type of cell • Stem cells wait for signals to tell them what to become • Until it receives a signal, it must wait patiently and divide slowly • When it receives a signal, begin to differentiate • The signals tell stem cell to turn on certain cell type it supposed to become

• These Super cell have a magic clinical potential in tissue repair • They represent the future relief of a wide range of incurable diseases • They could replace defective organ and tissues • They can restore the function of dysfunctional or non functional organs

Where do they come from?

Early embryonic stages Some Fetal tissues The Umbilical Cord Several Adult organs –Bone Marrow –Peripheral blood –Fat tissues –Etc…

Adult stem cell?

• • • • •

Every single organ has it’s own stem cell Bone Marrow Heamatopoietic stem cell (HSC) Endothelial stem cell (ESC) Mesenchymal stem cell (MSC)

Mesenchymal Stem Cells (MSCs)

• MSCs are adult stem cells from BM that can differentiate into multiple nonhematopoietic cell lineages.

• They can differentiate into osteoblast, adipocytes, chondrocytes, myocytes, cardiomyocytes, astrocytes, oligodenrocytes and neurons.

• They have potential to down regulate and inhibit immune response in both recognition and elimination phases

• Possible clinical application proposed for MSC include: • stem cell transplantation • Stem cell strategies for the repair of damaged organ and gene therapy • MSCs due to their immunomodulatory potential theoretically, they can be used allogenically

The role of Mesenchymal Stem Cells in relationship with injured somatic tissue and non-immune cells

CAN STEM CELLS BE ISOLATED AND USED?

If so under what conditions and restrictions?

The low frequency of MSC in bone marrow necessitate the in vitro expansion prior to clinical use • We evaluated the effect of long term culture on the senescence of these cells • Surprisingly , MSC loses their characteristic after several passages Therefore: It is much better to consider them for therapy early on

BM MSC culture (passage 6)

The goal of our stem cell therapy studies

• Assessing the safeness of the stem cell injection • The patients improvement from a clinical point of view • The degree of damaged tissue repair

Mesenchymal Stem Cell therapy for Multiple Sclerosis and Heart Diseases

Results of MS treatment

• 10 MS patients with secondary progressive disease has been transplanted • One patient improved 2.5 score in EDSS (expanded disability status scale) • 4 others showed some degree of improvement • 5 patients after MSCT has not hastened disease progress

Results of MSCT in Heart disease

Cardiac functional parameters of mean 18 month fallow up in test group Parameters Base line ± SD After MSC ± SD P value NYHA 2.75 ± 0.70 1.38 ± 0.51 .000

LVEF 38.75 ± 13 48.75± 6.4 .005

SPECT 11 ± 2 7.75 ± 1.1 .002

Cardiac functional parameters of mean 18 month fallow up in control group Parameters Base line ± SD After pro. ± SD P value NYHA 2.75 ± 0.70 2.13 ± 0.35 .049

LVEF 41.88 ± 8.42 42.50 ± 8.86 NS SPECT 10.88 ±1.95 9.75 ± 1.58 .007

Comparison of cardiac function in two groups.

Groups

NYHA LVEF SPECT before after before after before after

Test group

2.75 1.38 38.75 48.75 11 7.75

Control group P value

2.75 2.13 41.88 42.50 10.88

9.75

NS .005 NS NS NS .013

Potential Tumorigenicity of these cells

Finally

• It seems, like all other issues, – We must first consider all potential results and possibilities – BEFORE ANY INTERVENTION • Because – NOTHING COMES TO US WITHOUT A DEGREE OF RISK