Unit 8 - 6 Immunology

diabetes
chronic gn
pkd

graft from self

grafting from identical twin or clone

from nonidentical individual of same species

from different species

also called human leukocyte antigens (HLA); encoded in MHC locus on chromosome 6 in humans

function to present peptides to T cells

I: on APCs (DC, macrophage, B cell) (binds CD4+ helper)
II: on all nucleated cells (and platelets) [leukocytes, epithelial cells, mesenchymal cells) = bind w CD8+ CTL for killing

polymorphic (many diff alleles are present in the population)
an entire HLA locus is inherited from each parent
alll inherited alleles are expressed (called codominant expression)

human chromosome 6

you inherit one haplotype from each parent

choose donor w compatible blood type and closest match at HLA-DR (bc Dr is highly polymorphic and highly expressed)

bc A/B are very polymorphic while C is not

anatomical compatibility, need to minimize organ storage time etc. may override the benefits of HLA matching (for unknown reasons rejection against liver transplants is weaker than might be expected)

Either recipient’s T cells cross react with allogeneic MHC/peptide complex (direct recognition)
Or recipient’s DCs process allogeneic MHC molecules into peptides, and present these peptides on self MHC (indirect recognition)

recipient’s T cells cross react with allogeneic MHC/peptide complex (graft presents the antigen)

Direct = Donor APC (D=DAPC)

recipient’s DCs process allogeneic MHC molecules into peptides, and present these peptides on self MHC

Antibodie mediated (type II) due to preformed antidonor antibodies in the transplant recipient. Occurs within minutes after transplantation

Cell mediated due to cyotoxic T lymphocytes reacting against foreign MHCs. Occurs weeks after transplantation. Reversible w immunosuppressants such as cyclosporine and OKT3.

T-cell and antibody mediated vascular damage (obliterative vascular fibrosis); occurs months to years after transplantation. Irreversible. Class I-MHC (non self) is perceived by CTLs as class I-MHC (self) presenting a non self antigen

Infiltrates of plasma cells and eosinophils, concentric endothelial proliferation, fibrosis of graft

Inhibits de novo guanine synthesis and blocks lymphocyte production

Anti-CD3 monoclonal ab opsonizes and causes complement mediated lysis of T cells (used to tx acute rejection)

MOA: Blocks differentiation and activation of T cells by inhibitng calcineurin, thus preventing the production of IL-2 and its receptor.

Clinical use: Suppresses organ rejection after transplantation; selected autoimmune disorders

Toxicity: Predisposes pts to viral infections and lymphoma; nephrotoxic (preventable w mannitol diuresis)

Increased incidence of infections

Increased incidence of tumors especially those produced by oncogenic viruses

Cyclosporine is nephrotoxic

Immunologically competent donor cells placed into a immunodeficient recipient; memory T cells (CD4+Th1s, CD8+ CTLs) transplanted into an irradiated recipient

Immunocompetent T cells (Graft) recognize the recipients HLA antigens as foreign and react against (vs) the recipient (host)

thus HLA matching VERY important in bone marrow transplantation (injected BM hones to irridated/removed BM)

Major organs affected = skin (rash), liver (jaundice) and intestines (bloody diarrhea).