Seminar 3 - transplantation and stem cells

Transplantation

A graft or transplant is the transfer of living tissues, organs or cells from one site to another, either within the same individual or between different individuals

Main problem of transplantation

Host’s immune system identifies donor tissue as foreign and may reject it

Grafts classification

Autografts - from one part of the body to another

Isografts - between isogenic individual (recipient that is genetically identical)

Allograft - between genetically different individuals from the same species

Xenograft - between members of different species (high rejection due to IgM and cell mediated immunity)

Components involved in transplant rejection

Antigen presenting cells - dendritic, macrophages and B cells, present donor antigens to recipient T cells, can migrate from graft to lymph nodes → initiating rejection

T cells - central to rejection, recognise donor MHC by recognising donor APC or recognising peptides presented by host APC

B cells and antibodies - produce antidonor antibodies that fix complement, recruit neutrophils and cause vascular injury

NK and macrophages - contribute to inflammatory response and graft damage

Alloimmunity

Immune response against donor MHC (Human leukocyte antigen - HLA)

When an organ is transplanted, recipients immune system sees the donor MHC molecules as foreign and launches immune attack

Triggers cell mediated immunity (t cells attack donor cell, activate macrophages…) and humoral (b cells produce antibodies, binds to graft blood vessels and recruit immune cells)

Alloantigens

Molecules causing immune recognition of donor tissue (MHC proteins, CD43, blood group antigens…)

Highly polymorphic → more variations → more chance of rejection

Histocompatibility antigens

MHC haplotype - set of MHC allelles inherited from each parent

Minor histocompatilitity antigens → can still cause rejection but slower

Cytokines upregulate MHC, increasing immunogenicity

Recognition of alloantigens

Direct presentation - donor MHC is directly recognised by T cells, both CD4+ and CD*+ T cells are involved

Indirect presentation - donor MHC is processed by recipient APC and presented via recipient MHC, basically processed like any foreign antigen, only involves CD4+ T cells

Experimental animals → evidence of role of T cells in rejection

Removal of thymus leads to inability to reject transplant

Removing T cells prevents rejection, adding them back restores rejection ability

Antibodies cause graft damage and macrophages are involved in inflammation

Hyperacute rejection

Minutes to hours

Caused by pre-existing antibodies in recipient

When organ is connected to recipients circulation, the antibodies immediately bind to donor endothelial cells

This activates complement system and leads to endothelial damage, platelet activation, thrombosis and necrosis of graft tissue

Irreversible and requires removal of graft

Acute rejection

Days to weeks post transplant

Type 1 - Cell mediated → CD8+ cytotoxic T cells attack graft cells directly, CD4+ helper T cells recruit macrophages, this response targets foreign MHC molecules

Type 2 - Antibody mediated → new antibodies are formed after transplant, binds to donor antigens → complement activation, inflammation and vascular injury

Can be treated

Chronic rejection

Months to years after transplantation

Slow, progressive immune response, often involves both T cells and antibodies

Can be caused by low level persistent immune activation, ischemia-reperfusion injury or repeated minor episodes of acute rejection

Resistant to treatment, may require re-transplantation

Bone marrow transplantation

For hematologic diseases (leukemis, anemia, SCID)

Recipient is immunologically suppressed before grafting

Risk - GVHD → donor bone marrow contains immunocompetent cells → graft may reject host → causes graft vs host diseases

GVHD

Occurs when donor T cells recognise recipient cells as foreign

Symptoms - diarrhea, fever, weight loss, rash, erythema, joint pain and death

Organ transplants

Kidney - diseases like diabetes and nephritis, high success and survival rate, most common

Liver - treats congenital defects and damage from viral (hepatitis) or chemical agents

Pancreas - can treat diabetes, can be combined with kidneys

Skin - used for burns, high risk of rejection due to some use of foreign skin

Xenotransplantation barriers

Natural IgM antibodies rapidly reject xenografts

What is immunosuppression

Deliberately reducing the activity of the immune system, primarily to prevent it from attacking a transplanted organ or tissue

Main immunosuppressant drugs

Cyclosporins - inhibit T cell activation (by inhibiting calcineurin - enzyme for T cell activation), prevents T cells from attacking transplant organ

Azathioprines - inhibit DNA synthesis and affect T&B cells, bone marrow suppression

Corticosteroids - like prednisone, anti inflammatory, suppress gene transcription of cytokines, reduce T cell activation and macrophage activity

Role of monoclonal antibodies in immunosuppression

Depleting immune cells (especially T cells), blocks activation pathways, inhibit cytokines, reduce inflammation and immune memory

Anti T cells antibodies target T cell markers to deplete and block T cells

IL2 receptor antagonists block receptor on activated T cells, prevent proliferation

Costimulation blockers prevent full activation of T cells

Stem cells

Undifferentiated cells with self renewal and differentiation ability

Sources - adult tissues, cord blood and embryonic tissue

Hematopoietic stem cells (HSC)

Originate in bone marrow

Differentiate into all blood cells

Used in treating leukemia, lymphoma and immune disorders

Bone marrow transplant

Involves transferring hematopoietic stem cells from a donor into recipient

The stem cells repopulate the bone marrow and restore the production of blood cells

Patient recieves high dose chemo or radiation therapy to destroy diseased or cancerous marrow, donor stem cells are then infused intravenously, cells migrate to bone marrow and engraft

Umbilical cord blood stem cells

Stem cells are harvested from the blood remaining in the placenta and umbilical cord after childbirth

They are rich in hematopoietic stem cells

Easy to collect, lower risk of GVHD (immature immune cells)

Adipose (fat derived) stem cells

Adipose tissue contains mesenchymal stem cells that can differentiate into bone, cartilage, fat and muscles

They are harvested via liposuction and are then isolated and purified in a lab

Pluripotent stem cells

Derived from inner cell mass of blastocyst and excess embryos created during IVF

They are pluripotent (into any cell type of body), can divide indefinately

Adult stem cells

Found in developed tissues throughout the body, involved in maintenance, repair and regeneration of tissues

They are multipotent (limited range of cell types, usually related to tissue of origin)

Self renewable, low risk of rejection and less tumorigenic

Mostly used for bone marrow transplants, autoimmune diseases, regenerative therapy…

Induced pluripotent stem cells (iPSC)

Adult somatic cells that are genetically reprogrammed to become pluripotent

Cloning

Making an exact genetic copy of an organism or call

Reproductive cloning (Dolly) → nucleus from somatic cell is inserted into enucleated egg, egg divides, forms embryo which is inserted in surrogate

Therapeutic cloning - used to create personalised embryonic stem cells which are genetically identical to donor

Immunology of gestation

Mentions why the fetus isn’t rejected by the mother

The placenta acts as an immunological shield by filtering anti MHC antibodies

Trophoblast is the outermost layer of fetal tissue and is in direct contact with maternal blood, it lacks strong MHC expression

Gestation

Placenta secretes neurokinin B bound to phosphocholine, this modifies how the maternal immune system perceives the placenta (helps fetus “hide”)

Fetal lymphocytic suppressor cells inhibit maternal cytotoxic T cells by inhibiting IL2 → this helps reduce the chances of immune attacks against the fetus

Trophoblast express HLA-C which highly immunogenic and helps them avoid being targed

Maternal IgG antibodies are actively transported across the placenta to provide passive immunity to the fetus

IgM antibodies (against ABO bloodtypes) are too big to cross the placenta and therefore doesnt harm the fetus