• graft rejection is immune reaction.
• autografts are accepted and allografts are not
• second grafts are rejected more rapidly due to memory

• to be able to minimize rejection w/o suppressing the entire immune response.
• blood transfusion does not have the problem of suppressing the immune response, because it becomes degraded
• kidney has to stay with the patient for the rest of their life, therefore the immune response will need to be suppressed.

• Autograft- w/in the same individual
• isograft- from genetically identical donor
• allograft- from genetically different members of the same species
• xenograft- from a different species.

• kidney
• lungs
• heart
• bone marrow
• cornea
• pancreas

• occurs quicker than the first, if using the same tissue
• if a different strain of tissue is used, than the reaction will proceed as if it is the first time.

• The grafted epidermis will begin to have blood vessels that will go to the site
• in 3-7 days revascularization of the blood vessel will occur
• 7-10 days neutrophils will come by and healing occurs
• day 12-14 resolution

• first set of rejection revascularization occurs in 3-7 days than the onset of cellular infiltration in 710 days which leads to thrombosis and necrotic tissue.
• second set of rejection cellular infiltration happens rapidly in 3-4 days leading to thrombosis and necrosis in 5-6 days.

• A mouse undergoes a graft having anti cd8 bind to t cytotoxic cells, that won't let them kill bust the mouse still died at 15 days
• if anti CD4 was used than the mouse lived upto 30 days
• when both were used the life was extended to 60 days

• histocompatability based on antigenically similar individuals. Want tissues to not induce immunologic rejection
• Recipient donor are typed for blood group antigens that are present on RBCs, epithelial cells, and endothelial cells.

HLA (hla-a, hla-b, and hla-dr)

ABO (+/-)

• HIV
• heptatitis B (HBsAg)
• Heptatis C (HCV)
• also CMV, HTLV-1, syphilis, Epstein-barr virus, and HTLV-2 b/c immune system has to be suppresead so cannot fight these diseases.

Response to ABO antigens (and/or MHC class I/II molecules) expressed by endothelial cells.

• preexisting ab to A/B antigens in recipients bing A or B ag on enddothelial cells of transplanted organs and induce acute rejection
• caused by pre-existing ab to MHC I/II molecules too, which can arise from pregnanct, blood transfusion or previous transplantation.

• blood groups must match
• microcytoxicity test

test to see if there is a presence or absense of various MHC alleles

• taking the blood cells from the potential donor and recipient into a microtiter plate, ab specific for various class I and Class II MHC alleles are added to different wells. After incubation complement is added and cytotoxicity can be assessed by the uptake or exclusion of various dyes.

a) What happens as the amount of mismatched MHC increases?

b) Which mismatch MHC can there be more of?

a) Usually identical twins have no mismatched MHC and siblings may have 1 or 2, so they have a greater chance of survival than an allograft person who may have anywhere from 3 to 6...the more mismatched the less survival

b) There can be more mismatched MHC I.

• sensitization
• dendritic cells in graft may act as APC, along with others
• host effector cells can migrate
• donor cells can migrate to periphery and present graft antigens there.

Cell-mediated graft rejection.

What are the two stages?

Sensitization Stage: T cells are stimulated

   - antigen-reactive lymphocytes proliferate

   - most proliferation occurs in CD4 T cells

Effector stage: T cells attack the graft

   - delayed-type hypersensitivity (INF-gamma attracts

     macrophages)

   - CTL-mediated cytotoxicity

   - cytokines plays a central role.

varies with the graft

What is the pace of effector cells in skin, eye kidney and heart?

Effector cells are usually produced in the lymphoi tissue and then circulate back to graft.

skin- vasulature restored gradually

kidney or heart- immediately

eye- does not encounter immune cells.

• APC presents antigen to TH cell which releases IL-2, IL-4, IL-5, and IL-6
• T cells during DTH is activated by IL-2 which releases IFN gamma that activates macrophage to release lytic enzymes. Tdth also release TNF beta causing cytotoxicity. IFN gamma and TNF beta both increase MHC expression
• IL 2 activate CD8+ Tc cells that attach to the class I MHC alloantigen of the graft and undergo membrane damage. IL 2 also activates CD4+ Tc cell which also undergoes membrane damage
• IL2,4,5,6 activates  B cell to proliferate secreted antibodies that activate complement
• NK cell or macrophage Fc receptor attach to the ab undergoing ADCC

a) What is hyperacute rejection?

b) How quickly does it occur?

c) what is activated?

d) How can this be prevented?

e) Who is suspetible?

a) having preexisting ab to graft ag (complement)

b) occurs rapidly, before vascularization

c) neutrohils and complement

d) cross match

e) people who received repeated blood transfusion, have multiple pregnancies (exposure to paternal Ag), and have had previous grafts.

Transplant rejection vs. GvH.

What is the difference?

• in transplant rejection the t cells attack the transplant
• in graft vs. host, transplanted bone marrow produce t cells that attack the recipient's tissue.

Nonspecific agents

- general suppresion of all Ag

- put patient at risk of infection and cancers

Agents used to slow proliferation

- also affects any rapidly diving non-immune cells (can have life threatening complications)

corticosteroids

- suppress inflammation

Fungal metabolites

- more specific (inhibition of IL2 transcription)

total lymoid cross-irridiation

- note the bone marrow (cells ilwl be renewed)

Monoclonal antibodies

• can delete populations of reactive cells
• can block costimulatory signals leading to anergy
  - looking to block TCR, CD40L, block CD28, CTL-4, JaK pathway, calnexin and the cell cycle.

Allograft Tolerance

a) What tissues in the body do not have alloantigens?

b) Where are the sequestered sites in the body?

c) how can allograft tolerance occur?

a) cartilage and heart valves

b) areas absent of lymphatic vessels, cornea of the eye, brain, testes, and uterus.

c) early exposure to the antigen during the organism's development.

Clinical Cases

a) How common are kidney transplants?

b) Is the recipient sensitized to other transplants?

Clinical Cases

a) Before grafting for a bone marrow transplant, what does the recipient have to undergo before?

b) What is most common in 50-70% of the transplant?

c) What cytokine is key?

d) What are possible treatments?

a) Recipient needs to have their immune system suppressed.

b) graft vs. host disease is most common

c) tnf-beta

d) immunosuppresion and donor t cell depletion (partial; some activity needed against host t cells)

Clinical Cases

a) Is heart surgery successful?

b) how is mhc matching?

c) what disease is the transplanted heart prone to due to what reason?

a) Very successful

b) not feasible

c) prone to coronary disease to due massive immunosuppresion.

Clinical Cases

a) How often are lung transplants performed?

b) What other transplant is typically performed with a lung transplant?

a) rare

b) heart

Clinical Cases

a) How succesful are liver transplants?

b) what is it resistant to?

c) Is the surgery simplistic or difficult?

a) parts have been grafted successfully.

b) resistant to ab-mediated cytotoxicity but not to GvHD

c) The surgery is relatively difficult.

Clinical Cases

a) What part of the pancrease is transplanted?

b) How often is this transplant done?

a) functional parts (islet cells)

b) rare transplant

Clinical Cases

a) Skin transplants are typically derived from where?

b) Is immunosuppression typically used?

a) autologous burn victims

b) hard due to vulnerability to infection.