Transplantation Pathology Kristine Krafts, M.D.

Transplantation Outline Introduction Graft compatibility Graft rejection Types of organ transplantation

Transplantation Outline Introduction

Definitions Transplantation the moving of cells, tissues, and organs from one site to another Graft the transplanted organ Donor person from whom graft is taken Recipient (host) person who gets the graft

Transplantable Things Kidney Pancreas Heart Lung Liver Bone marrow Intestine Skin Cornea

Transplantation Problems Surgical difficulties Graft rejection Organ shortage

Transplantation Outline Introduction Graft compatibility

Compatibility Rejection recipient recognizes graft as foreign, and destroys it Autograft within same person Isograft between identical twins Allograft between genetically different people Xenograft between different species

Histocompatibility Histocompatible: antigenically similar Histoincompatible: antigenically different MHC antigens are the most important ABO antigens are also important

HLA Complex Gene collection on chromosome 6 Three regions: class I, class II, class III Class I gene products expressed on nearly all cells present antigen to TC cells Class II gene products expressed on antigen-presenting cells present antigen to TH cells

MHC genes on chromosome 6 = “haplotype” ♂ ♀ ♂ ♀ MHC genes on chromosome 6 = “haplotype”

HLA genes are inherited as sets (haplotypes) ♂ ♀ parents four possible haplotype combinations in children

HLA genes are polymorphic ♂ ♀ A B C DR DQ DP 1 7 w3 2 1 1 Dad’s HLA genes 2 8 w2 3 2 2 3 44 w4 4 1 3 Mom’s HLA genes 11 35 w1 7 3 4

If HLA genes were foods… ice cream yum yum pop fruit cookie veggie a b Dew haplotypes Vault c d

HLA genes are codominantly expressed

HLA Matching The more matching alleles between donor and host, the better! Matching the class II antigens is more important than matching the class I antigens. One or two class I mismatches = no big deal One or two class II mismatches = big deal Mismatches in both class I and II = very big deal

time after transplant, months 100 number of mismatches Class I Class II 1 or 2 3 or 4 graft survival, % 50 3 6 12 time after transplant, months

Transplantation Outline Introduction Graft compatibility Graft rejection

Graft Rejection Any two people (except identical twins) will express some HLA proteins that are different. Every recipient will recognize, and react against, at least some foreign antigens in the graft Rejection is complex, with lots of killing mechanisms.

How does rejection happen? T-cell-mediated rejection Antibody-mediated rejection

CTL Killing

Antibody-Mediated Rejection Preformed antibodies: within hours Newly-made antibodies: days – years later

Clinical Types of Rejection Hyperacute rejection Acute rejection Chronic rejection

Hyperacute Rejection Within hours Preexisting anti-donor antibodies Rare these days

Acute Rejection Starts at about 10 days Cell-mediated

Chronic Rejection Months to years after transplant Humoral and cell-mediated mechanisms Hard to prevent Hard to treat

Transplantation Outline Introduction Graft compatibility Graft rejection Types of organ transplantation

Kidney Transplantation Diabetes, glomerulonephritis, congenital disorders Most commonly transplanted organ Problems: host sensitization post-transplant malignancy

Heart Transplantation Cardiomyopathy, myocarditis, congenital defects, ischemic disease Must use heart-lung machine Problems: organ shortage maintaining graft before transplant post-transplant lymphoma

Bone Marrow Transplantation Leukemia, lymphoma Find living donor (easy) that matches (hard) Massive chemo/radiation first Problem: GVHD

Graft-vs-Host Disease Donor T cells see recipient as foreign! Attack skin, GI, liver Treat with immunosuppressive drugs Or, partially deplete donor marrow of T cells

Graft-vs-host disease, skin lesions