Transplantation Immunology

Haris Saddique

MPhil Scholar

Department of Biotechnology

University of Malakand

Kpk , Pakistan

• Introduction• Types of grafts, • Transplantation antigens• Mechanisms of graft rejection• Tempo of Rejection• Graft versus Host Reaction (GVHR)• Prevention of rejection

POINTS TO BE DISCUSSED

INTRODUCTION

Transplantation: the process of taking cells,

tissues, or organs from one individual and placing them into a different individual or different site of the same

individual

Graft: transplanted cells, tissues, or organs.

Donor: the individual who provides the graft. Recipient: the individual who receives the

graft. Also called the host.

Types of Grafts

• Autologous or autograft (self)• e.g., BM, peripheral blood stem cells, skin, bone

• Syngeneic or isograft (identical twin)

• Allogeneic or allograft (another human except identical twin)

• Xenogeneic or xenograft (one species to another)

• Major histocompatibility antigens (MHC molecules)

• Minor histocompatibility antigens• Other alloantigens

Transplantation antigens

• Is located on short arm of chromosome 6• It includes 3 regions: class Ia (loci A, B, C) class Ib

(loci E, F, G, H), class II (loci DR, DQ, DP) and class III

• Genes of class Ia and class II are highly polymorphic, while those of class Ib and class III are not

• Polymorphism means occurence of several allelles i.e genes encoding various MHC antigens located at the same locus

MAJOR HISTOCOMPATIBILITY COMPLEX (MHC)

Map of Human MHC

MAJOR HISTOCOMPATIBILITY ANTIGENS

• Histocompatibility antigens are expressed on all

nucleated cells (class I) and on APC,

B cells, monocytes/macrophages (class II)

• They are targets for rejection

• They are inherited from both parents as MHC

haplotypes and are co-dominantly expressed

• They also participate in rejection but to lesser degree

• Disparity of several minor antigens may result in rejection, even when MHC antigens are concordant between donor and recipient

• They include normal cellular constituents• They are peptides derived from polymorphic

cellular proteins bound to MHC class I molecules

MINOR HISTOCOMPATIBILITY ANTIGENS

• Also cause grafts rejection, but slow and weak

• Mouse H-Y antigens encoded by Y chromosome

• HA-1 ～ HA-5 linked with non-Y chromosome

OTHER ALLOANTIGENS

• Human ABO blood group antigens • Some tissue specific antigens

– Skin ＞ kidney ＞ heart ＞ pancreas ＞liver

– VEC antigen – SK antigen

Rejection

• First Set Rejection• Skin graft in mice 10-14 days

• Second Set Rejection• Skin graft in mice in 3-6 days

MECHANISM OF ALLOGRAFT REJECTION

The immune responses in allogeneic

transplantation: T cell mediated rejection of allograft Antibody mediated rejection of allograft NK cell mediated rejection of allograft

T cell mediated rejection of allograft

(mechanism of cellular immunity)

1) Recognition of alloantigens

2) Activation of T cells and rejection of allograft

Alloantigen Recognition

• Direct presentation (Donor APC) • Unprocessed allogeneic MHC

• Indirect presentation (Host APC)• Processed peptide of allogeneic MHC

• Direct recognition ------acute rejection

• Indirect recognition ------chronic rejection

Recognition of alloantigen

Direct recognition of alloantigen

• Recognition of an intact MHC molecule in the graft by T cells.

Indirect recognition of alloantigen • the donor MHC molecules may be processed

and presented by recipient APCs that enter grafts, and the processed MHC molecules are recognized by T cells like conventional foreign antigens.

Major Histocompatibility Complex (MHC)•Class I HLA A, B, C bind to TCR on CD8 T-Cell•Class II DR, DP, DQ bind to TCR on CD4 T-Cell

Activation of T cells and rejection of allograft

Host T cells may be activated by both direct recognition and indirect recognition

• Direct pathway : CD4+T ---- Th CD8+T ---- CTc ---- killing graft cells

• Indirect pathway : CD4+T ---- infiltrate the graft and recognize

donor alloantigens being displayed by host APCs that have entered the graft ---- Th

CD8+T ---- can not directly kill the foreign cells in the graft

Antibody-mediated rejection of allograft (mechanism of humoral immunity)Ⅰ. Complement activated by antibody involved in transplantation rejection

Ⅱ. Antibody participate in transplantation rejection through ADCC and opsonization

Antibody bound to the surface of infected cell is recognize by igG receptor on the surface of phagocytic cell e.g NK Cells

NK cell mediated rejection of allograft

• NK have receptor for allogeneic MHC proteins of graft

• CKs secreted by activated Th cells can promote NK activation.

• Participate in transplantation rejection through ADCC

Tempo of Rejection

• Hyperacute– Minutes to hours– Preexisting antibodies (IgG)Intravascular thrombosis– Hx of blood transfusion,

transplantation or multiple pregnancies

• Acute Rejection– Few days to weeks– CD4 + CD8 T-Cells– Humoral antibody response– Parenchymal damage &

Inflammation

• Chronic Rejection – Chronic fibrosis – Accelerated arteriosclerosis– 6 months to yrs– CD4, CD8, (Th2)– Macrophages

Not Applicable

10 – 30 DaysLysis of donor stem cells

30 days – 6 months Lysis of donor stem cells

Solid Organ Stem Cell

Graft versus Host Reaction (GVHR)

When grafted tissue has mature T cells, they will attack host tissue leading to GVHR.

Major problem for bone marrow transplant. Methods to overcome GVHR:

Treat bone marrow to deplete T cells. Use autologous bone marrow. Use umbilical cord blood

Prevention & Treatment of Allograft Rejection

• ABO Compatible (Prevent hyperacute rejection in solid organs) (Prevent transfusion reaction in BM/PBSC)

• MHC allele closely matched

• Calcineurin inhibitors– Cyclosporine binds to Cyclophillin– Tacrolimus (FK506) binds to FK Binding Proteins (FKBP)– Calcineurin activates Nuclear Factor of Activated T-Cells (NFAT)– NFAT promotes expression of IL-2

• IMPDH Inhibitors (Inosine Monophosphate Dehydrogenase)– Mycophenolate Mofetil (MMF)– Inhibits guanine nucleotide synthesis– Active metabolite is Mycophenolic acid (MPA)

THANKS FOR YOUR ATTENTION

&

HAVE A NICE DAY