Allogeneic  Transplant

Transplant from a genetically matched donor

Syngeneic Transplant

Transplant of tissue between genentically identical individuals (ie identical twins)

Most Common Allogeneic transplants in US

• Kidney
• Heart
• Liver
• Lung
• Pancreas
• Cornea
• (recently hand, face etc)
• Hemotopoetic stem cells (HSC)  (bone marrow)

Allogeneic transplant grafts that

DON'T

require immunosuppression for graft survival

Non-vascularized tissues 

i.e.

• Cornea
• Bone
• Joint

Transplant outcome determined by:

• Antigeneic disparity between donor and host
• Donor immune response
• Immunosupressive regimen
• Condition of the graft (ie living related better than cadaveric)

Transplantation rejection in solid organs

mediated by

Allo-reactive recipient T cells recognizing non-self MHC via 2 Tcell recognition mechanisms:

• Direct allorecognition (donor APC, expressing donor MHC, activate recipient T cells) ie recipient T cells DIRECTLY recognize donor MCH
• Indirect allorecognition: RECIPIENT APC presents donor Ag to recipient T cells ie recipient T cells  recognize DONOR antigen presented by recipient APC
• In BOTH cases, primed T cells invade graft

Risk factors for solid organ transplant rejection

Solid Organ Rejection

Hyperacute

• Occurs in minutes to hours
• Mediated by recipientantibodies and complement
• Recipient antibodies  recognize graft antigens  (ie natural ABO ags etc), fix complement etc
• Response is anamestic
• Pathology shows PMNs and thrombi

Solid Organ Rejection

Acute

ABO-incompatibility and

Transplant Outcome

Solid organ transplants (ie kidney, heart, lung, pancreas) require ABO match EXCEPT:

• infants (have not been exposed to bacteria to develop IgM that is ABO ag) receiving heart or liver
• Renal tissues weakly express A ag thus some cross-ABO renal grafts may succeed

Non vascularized tissues can be transplanted across ABO:

• Cornea, bone, joint, stem cells (HSC)

Pre transplant screening  for presence of anti-donor HLA antibodies

• Predicts hyperacute and acute (accelerated) rejection
• Screening is done against a panel of potential donors
• Result is expressed as percent reactive antibodies (PRA)
• Groups at risk for high PRA are those that have been exposed to non-self HLA ags in past ie            -recipients who have had multiple previous blood transfusions and multiparous women

Stem Cell transplants (HSC)

Conditions Treatable with HSC

ALL REQUIRE CHEMOTHERAPEUTIC ABLATION  to kill tumor and allow accpetance of HSC except SCID*

• Malignancy ie leukemias and solid tumors
• Inborn errors of metabolism (ie Hurler's, osteopetrosis)
• Hematopoetic disorders ie hemoglobinopathies, aplastic anemia
• Primary Immune Deficiencies ie SCID*, CGD, XLHiIgM, WAS

Stem Cell transplants (HSC)

HSC Transplant Poor Outcomes

• Non-engraftment due to recipient's rejection of donor cells (chemotherapy conditioning/immune ablation of recipient not only eradicates malignancy but improves engraftment by decreasing host response to graft)
• Graft vs host disease- donor (GRAFT) cells recognize recipient (HOST) tissues as non-self (improved/prevented by post transplant immune suppression and t cell depletion of graft)

GVHD

• Acute vs chronic
• GOOD in terms of decreasing risk of cancer relapse (graft vs leukemia effect)
• If HSC transplant is successful, doesn't require lifelong immune suppression (differs from solid organs)

GVHD risk

(highest to lowest)

1. Mismatched (including haplo-identical from relative as by definition is able to recognize other parents' T cells as non-self)
2. Matched unrelated
3. Unrelated Umbilical Cord Blood (naive t-cells won't react)
4. Matched 1st degree relative
5. Syngeneic

HSC in SCID

• IMMUNOLOGIC EMERGENCY (sooner transplant better chance of engraftment, less chance of infection)
• 95% survival if transplanted < 3 mos of age
• Survival rapidly declines after 6 mos of age due to opportunisitic infection and non-engrafment

Immunosuppressive Strategies

for Transplantation

Multiple drugs to hit multiple pathways:

(see p 558 for illustration of sites of action)

• Block T cell activation

1. Calcineurin antagonists ie Cyclosporin, Tacrolimus
2. Cytokine signal transduction blockers ie Sirolimus
3. Corticosteroids
4. Anti T Cell antibodies ie anti-CD3, ATG

• Inhibition of T cell proliferation

1. Nucleotide synthesis inhibitors ie azothiaprine, mycyophenolic acid etc