Tolerance and transplantation

Immunogen or tolerogen: (factors the favor immune vs tolerance response) [physical form, route of injection, dose of antigen]

Tolerance is favored when: (2 reasons)

• Lack of adjuvant 

• Long term persistence of antigen 

• Low level of costimulation

Central tolerance

deletion of lymphocytes with receptors that recognize self Ag before they mature during lymphocyte development: B cells bone marrow(bone marrow) ; T cells (thymic selection (affinity model, use of mTEC)

Issues with tolerance: 

• Leaky tolerance 

  • reasons : not all self-Ag are expressed in central lymphoid organs, weakly reactive cells, genetic defects impact apoptosis

Peripheral Tolerance

Deletion, anergy, or induction of regulatory function in T cells recognizing self Ag

Treg cells [what are the molecules on the cell surface and]

• Highly specific to an antigen 

• Molecules CD25+, CTLA-4 [it is present in most but higly active] (co-inhibitory molecule → decrease in proinflammatory molecules), IL-2R, FoxP3

How to get Treg 

• (central) Natural Treg = In the thymic selection → 

• (peripheral) Induced Th = cytokines like TGF-B  and IL-2 switch helper into T reg cells 

Function of Treg: (inhibitory cytokines & bystander suppression) 

• Treg interacts with APC’s Ag-MHCII complex it can down regulate other helper t cells on the APC surface 

• Cytolysis: Perforin, granzyme, FasL

B regulatory cells [what do they secrete]

• Secrete IL-10, IL-35, TGf-

• Turn on Treg 

• Engagement w/ Th17 cells can downregulate their function 

Myeloid derived suppressor cells

• Immature group of myeloid cells (granulocytes and monocytes) 

• They are producing inhibitory cytokines 

• In the case of cancers it shows down antitumor t cells —> poor prognosis

Methods of Tolerance for specific sites in the bidy {3 reasons}

• Antigen sequestration 

  • Lack of lymphatic drainage (anterior and lens of eye) 

  • Ags are isolated from interaction w/ immune cells 

• Restricted immune entry : blood brain barrier (stromal cells line blood vessels) 

• Limited immune cells present 

  • Few immune cells (cornea) 

Immune tolerance in pregnancy [3 exmaples]

• Palceneta = immunological barrier 

• Separate blood systems

• T reg

• Syncytium = fused placental cells so no immune cells or maternal blood can enter

Syncytium

fused placental cells so no immune cells or maternal blood can enter

Types of Transplantation: 

Xenotransplantation: 

• Testes and kidney survived in humans from chimpanzee

Matching in transplantation: 

• Blood group Ag difference = most intense graft rejections 

• MHC compatibility (parents and siblings are first choice 

• Cross matching = blood test → circulating Abs especially to HLA

Anti rejection drugs

allow organ transplants between completely mismatched people

Luminex bead-based screening assays

unique HLA antigen on each bead, then detect fluorescent marker for what specific bead it is

MHC/HLA compatibility

Siblings have a 25%

chance of MHC identity

 Parent-to-child grafts

have a 50% MHC match(they get one allele from each parent)

Certain organs have higher rate os success: [and then certain combos]

• Cornea transplant are successful bc they are immune privileged 

• Certain combinations of organs increase the odds of success 

  • Heart and lung 

  • Kidney and pancreas

Rejection first and second set (why. isthis faster): 

• First set = 12-14 days memory of the anti-graft response is generated 

Second set rejection = occurs much faster due to memory from prior graft → necrosis

Hyperacute

• rejection by preexisting antibodies 

• Occurs before grafted tissue revascularizes

•  Preexisting antibodies bind to graft cells and activate complement and ADCC

Acute rejection  (what are the two stages)

mediated by T cell response ; 7-10 days [the T cells have not seen the antigen in this T cell before]

• Sensitization stage 

  • APC present Ag

  • T cells activate and proliferate 

  • T cell expansion and Memory t Cells are created 

• Effector stage: 

  • Immune cells into graft tissue 

  • Inflammatory cytokines and cell-damaging chemicals 

  • Antibody production

Do memory T cell still require APCs to activate

Yes but they dont require a storng costimulatory signal or as much antigen

Adoptive transfer and t cell neutralization experiments (what is the experiment) 

• t cells mediate graft rejection =  CD 4 more important than 8 but 8 is important too

• Adoptive transfer: take T cells from one mice and give it to another increasing the number of t cells and see how this would cause a response to the graft

Antibody depletion experiment : add antibodies that target the helper cells and deplete the t cellsChronic rejection:  with phagocytosis, degranulation

Chronic rejection: 

• Months-years later 

• Antirejection med not effective 

• Humoral and cell-mediated response

Graft versus host disease (GVHD) 

• Immune cells donate organ expand and attack recipient 

General immunosuppressive therapy - irradiation {what could it treat}

Irradiation of lymphoid regions to eliminate lymphocytes; wipe out recipient immune cells and add new immune cells → used to treat graft vs host disease and cancer 

General immunosuppressive therapies

Specific immunosuppressive therapies [blocking T cell function]

• mABs 

  • Basiliximab: mAB to cd 25

  • Cd 25 is a subunit to IL-2r

• Rituximab: mAb to CD20 on B cells

  • • mAb binding leads to cell death

Belatacept

 soluble CTLA-4 protein → T cell anergy, used in kidney transplantation

Problems w/ immunosuppression 

• Drug toxicity 

• Increased infections 

• Increased endogenous viral infections (dormant infections) Bk polyomavirus → target graft