Renal Transplantation . Azim Gangji MD FRCPC FACP McMaster University. Objectives. Overview of Immunology Cross match test Immunosuppressive Medications Rejection Antibody Mediated Rejection Acute Cellular Rejection Causes of Allograft Failure Surgical Complications
Azim Gangji MD FRCPC FACP
3D structure of MHC Class II Molecule
class II MHC molecules. The schematic diagrams and models of the crystal structures of class I MHC and class II MHC molecules
Both types of MHC molecules contain peptide-binding clefts and invariant portions that bind CD8 (the 3 domain of class I) or CD4 (the 4 domain of class II).Schematic of MHC
Within the acidic endosomal compartment, the MHC proteins are fragmented into their constituent peptides. They are then transferred into the endoplasmic reticulum, loaded into the antigen binding cleft of MHC class II of the recipient and finally expressed on the cell surface of recipients APCs. This mechanism has been referred to as the "indirect allorecognition.“
However, this is of course the normal route by which T cells normally encounter antigen ie in context of self MHC.T Cell Recognition of Alloantigen: Indirect Pathways
Direct allorecognition of intact surface MHC molecules has only been demonstrated in allogenic transplantation
This pathway is thought to be of dominant importance during early acute rejection as engrafted organs contain a large number of passenger leukocytes.T Cell Recognition of Alloantigen: Direct Pathways
differentiate into effector cells whose function is to eliminate the antigens. B lymphocytes recognize soluble or cell
surface antigens and differentiate into antibody-secreting cells. Helper T lymphocytes recognize antigens on the
surfaces of APCs and secrete cytokines, which simulate different mechanisms of immunity and inflammation.
Cytolytic T lymphocytes recognize antigens on infected cells and kill these cells. (Note that lymphocytes recognize
peptides that are displayed by MHC molecules.) Natural killer cells recognize changes on the surface of infected
cells and kill these cells. It should be emphasized that native T cells (CD4 or CD8) are activated by professional
APCs. Effector CD8 T cells, not native T cells, can kill and infected cell expressing the specific peptide-class I
complex.B, T and NK Cells and Effect: Rejection
T and B
cell memoryImmune Activation and Rejection
0 0.5 1 2… 24 hours…. 3-4 days… 7 days...
Recipient’s serum + Donor lymphocytes (with defined HLA) + Complement, Incubate, add Eosin; remember here lymphocytes are just serving as cells that can be lysed; nil to do with the immune process/function
Signal 1: Engagement of the T cell receptor with the antigen peptide in the context of self major histocompatibility complex (MHC) class II molecule leads to the activation of the calcineurin pathway and results in the induction of cytokine genes (e.g., interleukin [IL]-2).
Signal 2: The costimulatory signal, involves the engagement of CD28 with members of the B7 family. This synergizes with signal 1 to induce cytokine production.
Signal 3: Interaction between cytokine production and its corresponding receptor leads to induction of cell division, probably through the target of rapamycin pathway. This constitutes signal 3.Immunosuppressant Action Overview
1. Gaston RS. Am J Kidney Dis. 2001;38(suppl):S25-S35.
2. Johnson C, et al. Transplantation. 2000;69:834-841.
3. Margreiter R. Lancet. 2002;359:741-746.
Gaston RS. Am J Kidney Dis. 2001;38(suppl):S25-S35.
Sirolimus increases CsA levels
Grapefruit juiceMetabolic Interactions That Increase CNI Levels
Inhibits proliferation of T and B cells and effect is mediated by AZA metabolites, 6-MP, 6-TU, 6-MMP, 6-TGNAzathioprine
Instead Sirolimus inhibits mTOR and blocks IL-2 mediated cell proliferation
mTOR activates protein that trigger cell cylcle G1 to S progressionSirolimus/Everolimus
Suppress production of numerous cytokines (IL-1, TNF, IL-2, chemokines, prostaglandins, proteases, NFK-B)
Also affect chemotaxis (neutrophilia)
Corticosteroids Side Effects
Cushingoid facial appearance
Growth retardation in childrenCorticosteroids
I always recommend drinking at least 6-8 glasses of fluid for the procedure!”
Surgical resident ?
Fishman NEJM 2007