Immune responsiveness in renal transplant recipients: mycophenolic acid severely depresses humoral immunity in vivo.
BACKGROUND
Current immunosuppressive drug treatments for renal transplant recipients result in high one-year graft survival rates. Despite adequate suppression of the immune response directed to the allograft, the immune system remains able to cope with many infectious agents.


METHODS
To define the influence of distinct immunosuppressive treatment protocols, primary and secondary cellular and humoral immune responses in groups of renal transplant recipients were studied: patient treated with prednisolone and cyclosporine A (P/CsA); with IgA CD3 monoclonal antibody as a rejection treatment superimposed on prednisolone and cyclosporine A (IgA CD3 mAb+P/CsA); and with prednisolone, cyclosporine A and mycophenolate mofetil (P/CsA/MMF).


RESULTS
Primary in vitro proliferative responses to the protein antigen keyhole limpet hemocyanin (KLH) were not significantly disturbed in P/CsA treated patients, or in IgA CD3 mAb+P/CsA and P/CsA/MMF treated patients. In vitro proliferative responses to the recall antigen tetanus toxoid (TT) were similarly unaffected. Antigen-specific antibody responses to immunization with KLH and TT were not affected by treatment with P/CsA, or by IgA CD3 mAb+P/CsA, but were severely disturbed in patients treated with P/CsA/MMF. All patients displayed a profound inhibition of the delayed-type hypersensitivity skin reactivity to KLH and recall antigens. Nevertheless, in most patients with P/CsA treatment, T cell infiltrates were observed in skin biopsies from the site of KLH challenge, while expression of intercellular cell adhesion molecule-1 (ICAM-1) expression in challenged skin was significantly decreased in these patients. The balance between T helper 1 and T helper 2 cells was unaffected by immunosuppressive treatments during one year of follow-up.


CONCLUSIONS
Immunosuppressive drug treatment with P/CsA inhibits delayed-type hypersensitivity skin reactions to both primary and frequently encountered antigens. Histological studies indicate an effect on ICAM-1 expression, leaving the influx of CD3pos T cells unaffected. Administration of a 10-day course of IgA CD3 mAb does not add profound immunosuppressive effects on the measured parameters. In contrast, addition of treatment with MMF profoundly decreases both primary and secondary humoral immune responsiveness in vivo. Finally, no effect of the studied immunosuppressive drugs on Th1/Th2 balance in vivo was measured.
Rentenaar
Rob J
RJ
Renal Transplant Unit F4-215, POI Box 22700, 1100 DE Amsterdam, The Netherlands.
van Diepen
Frank N J
FN
Meijer
René T
RT
Surachno
Sugianto
S
Wilmink
Joep M
JM
Schellekens
Peter Th A
PT
Pals
Steven T
ST
van Lier
René A W
RA
ten Berge
Ineke J M
IJ
D000293:Adolescent; D000328:Adult; D000917:Antibody Formation / Q000187:drug effects; D016572:Cyclosporine / Q000008:administration & dosage; D004359:Drug Therapy, Combination; D019040:E-Selectin / Q000032:analysis; D005260:Female; D006433:Hemocyanins / Q000276:immunology; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000517:prevention & control; D007074:Immunoglobulin G / Q000096:biosynthesis; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D007371:Interferon-gamma / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D016030:Kidney Transplantation / Q000276:immunology*; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology*; D011239:Prednisolone / Q000008:administration & dosage
D019040:E-Selectin; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D018799:Intercellular Adhesion Molecule-1; D015847:Interleukin-4; D007371:Interferon-gamma; D016572:Cyclosporine; D006433:Hemocyanins; D011239:Prednisolone; C032808:keyhole-limpet hemocyanin; D009173:Mycophenolic Acid