Lecture 26 & 27: Immunopharmacology Flashcards
What are the three main applications of immunosuppressive drugs?
suppression of rejection of transplanted organs and tissues (e.g. bone marrow)
suppression of “Graft-Versus-Host” disease (GVHD) which may arise from donor lymphocytes reacting against host, especially in bone marrow transplants
auto-immune diseases - examples include “lupus” (systemic lupus erythematosus), rheumatoid arthritis, psoriasis, ulcerative colitis, idiopathic thrombocytopenic purpura
Why do we use immunosuppressants?
during transplantation, we usually think of “rejection” in the context of host recognition of the donor organ
antigens may be recognized as “non-self” and elicit an immune response that attack the donor organ
however, this can also occur “in reverse”, if there are immunocompetent cells in the donor graft that mount an immune response against the host; the main tissues targeted are liver, skin, mucosa, gut
immunosuppressant drugs are used in both contexts
What is rheumatoid arthritis?
auto-immune disease primarily affecting the joints (but other tissues also)
What is lupus?
multi-organ auto-immune disease (characteristic rash on cheeks, but again many tissues are affected)
What are ulcerative colitis?
T-cell infiltration (auto-immune) and ulceration in the colon
What is psoriasis?
auto-immune disease leading to scaly patches pf skin
What are the key features of the immune response?
we will focus on the “specific immunological response”, not the innate immune response
key phases in the response are the induction phase and the effector phase
the induction phase includes recognition and presentation of foreign antigen, activation and proliferation of naive Th0-cells into Th1 and Th2 cells
the effector phase includes the cell-mediated T-cell responses (cells “killing” infected or foreign cells) derived from Th1 cells, and antibody-mediated responses derived from Th2 cells (leading to activation of B cells)
What are the critical steps/regulators are targeted by available immunosuppressant drugs?
inhibition of IL-2 production/action
inhibition of cytokine gene expression (glucocorticoids)
cytotoxicity (killing immune cells or preventing their maturation/expansion)
inhibition of nucleic acid synthesis
blockage of various T-cell surface receptors to prevent immune activation (e.g. antigen presentation machinery)
What are calcineurin inhibitors (e.g., cyclosporine, tacrolimus)?
activation of naive Th0-cells, and clonal expansion of T cells requires activation of several signaling pathways including the calcineurin-NFAT (nuclear factor of activated T-cells) pathway
activation of the T-cell receptor generates a Ca2+ signal, leading to activation of calcineurin (phosphate), and dephosphorylation of NFAT
cyclosporine and tacrolimus bind to their targets (cyclophilin, FKBP, respectively); these drug-bound targets suppress calcineurin – this suppresses the pathway that leads to IL-2 gene transcription
What is cyclosporine?
key detail of this mechanism is the inhibition of calcineurin by the cyclophilin: cyclosporin complex
this prevents NFAT-mediated gene transcription, leading to inhibition of T-cell maturation and proliferation (IL-2 is a major signal)
What is tacrolimus?
key detail of this mechanism is the inhibition of calcineurin by the FKBP: tacrolimus complex
similar to cyclosporine, this prevents NFAT-mediated gene transcription, especially important is the suppression of IL-2
What are proliferation signal inhibitors (e.g., rapamycin, AKA sirolimus)?
these drugs interfere with the downstream signals of IL-2 receptor activation
rapamycin binds to FKBP (same target as tacrolimus)
however, rapamycin-FKBP complex does not inhibit calcineurin, it inhibits a protein complex called mTOR (mammalian Target of Rapamycin)
mTOR is a major pathway responsible for promoting cell growth and proliferation
What is sirolimus/rapamycin?
key detail of this mechanism is the inhibition of mTOR by the FKBP: sirolimus complex
these effects suppress cellular responses to IL-2 receptor activation
What is FKBP?
FKBP is an acronym for FK506-binding protein
FKBP proteins are a family of proteins that are “peptidyl-proline cis-trans isomerases” (role in protein maturation); they also have a variety of endogenous binding partners
FKBRs and cyclophilins are part of the same larger protein family of “immunophilins” - all are proline isomerases
in addition to calcineurin and mTOR, other targets of these proteins include the ryanodine receptor and IP3 receptor (Ca2+ release channels)
What are cytotoxic agents?
cyclophosphamide (alkylating agent)
leads to cross-linking of neighboring bases; this interferes with DNA replication
most effective in rapidly dividing cells, so these drugs are useful in cancer treatment, and for suppression of rapidly dividing immune cells
