Tolerance and Immune Regulation

Immature B/T cells + foreign Ag =

tolerance

Medawar----- Immature =

Tolerance

Medawar-----Mature =

Activation

Self Tolerance

Property of both B and T cells

State of SPECIFIC unresponsiveness to self-antigen

Occurs at different stages of lymphocyte’s development

Immature cells are much more

Sensitive to signaling through BCR/TCR

Continuous exposure to antigen

Favors tolerance

Absence of co-stimulatory molecules

Induces tolerance

Central Tolerance

Tolerance induced in early stages of lymphocyte development

Clonal Selection Theory

Negative Selection

Central Tolerance Occurs in

Primary lymphoid organs

T cells that interact with a HIGH affinity

For self antigen in the thymus are deleted

AIRE (autoimmune regulator) responsible for thymic expression of self antigens

Derived from OUTSIDE thymus

B cells that interact with a HIGH affinity

For self antigen in the Bone Marrow are deleted

ANERGIC B cells

Can’t be activated to proliferate and or differentiate (eventually deleted)

Central Tolerance: Receptor Avidity

Used by BOTH T and B cells

Threshold of receptor signaling is MAJOR force determining mechanism of tolerance

Affinity of receptor for self Ag

Nature of Ag (multivalent vs. monovalent)

Ag concentration

Cell presenting the autoantigen (DC or Thymic Epithelial )

Expression level of BCR or TCR

Need for Peripheral Tolerance

Not all self-Antigens are expressed in thymus

Not all self peptides bind MHC

Self-antigen not present in high enough levels

Decreased affinity of TCR or BCR

Peripheral Tolerance Mechanisms

Anergy (Lack of co-stimulatory signal 2)

Cell Death ----FasL mediated

Tregs (natural or adaptive)

Peripheral Tolerance:Fas/FasL-Induced Cell Death

As (CD95) interacts with FasL (CD178)

Binding of Fas/FasL cause

Trimerization (Death domain activated)

Autoimmune Lymphoproliferative Syndrome =

Mutation in Fas

Immunologically Privileged Sites

Testes, eyes, brain, ovary, and placenta

Corneal transplants do not require MHC match

Cells express FasL: induce apoptosis of T cells or B cells

TGF-beta & IL-10 secretion (immunosuppressive)

T cell subsets regulate each other via

Cytokines

Clinical Application:

Transplantation

Autograft

Transfer of tissue from one area of body to another (same body)

Isograft (Syngeneic graft)

Transfer of cells/tissues between individuals of the same species and genetically identical (twins)

Allograft

Transfer of cells/tissues between individuals of the same species but genetically different

Xenograft

Transfer of cells/tissues between individuals of different species

Allograft Destruction by Immune Cells

Direct or Indirect Alloantigen Recognition

Direct Recognition

Host T cell recognizes combination of donor MHC and foreign peptide

Indirect Recognition

Host T cell recognizes combination of host MHC and foreign peptide.

Recipient APC presenting processed donor derived peptide

Cytokines & Perforin/Granzyme & antibody-mediated reactions

(Th1/CD8 and B cells form to result in donor graft destruction)

Hyperacute Rejection (hours)

Recipient has preformed antibodies (ABO or HLA) that attack donor graft vascular endothelium . Complement also plays a role in rejection

Acute Rejections (weeks to months)

Cellular and antibody mediated (vascular injury to graft). T cells often found

Chronic Rejection (year or longer)

Fibrosis and scarring with narrowing blood vessels plus immunopathology in the graft. Clinically a huge problem

Graft vs. Host Disease (GVHD, time varies)

Donor T cells in stem cell or bone marrow transplant attack the host

Immunosuppressive Agents

Suppress anti-graft immune response in recipient to solid-organ and Stem cell/BM transplants.

Combination of different agents used (COMES AT A PRICE)!

Steroids

Anti-inflammatory

Blocks production/secretion of cytokines, chemokines, adhesion molecules and inflammatory mediators

Cyclosporin/FK506 (Tacrolimus)/Rapamycin

Blocks signal transduction in T cells resulting in impaired synthesis of cytokines and decreased proliferation/differentiation

Antimetabolites

Anti-proliferative for T cells

Monoclonal and Polyclonal

Antibodies to T cells