Serial combination therapy: is immune modulation in multiple sclerosis enhanced by initial immune suppression?
BACKGROUND
Although the concept that an initial course of immune-suppression facilitates subsequent immune-modulation (such as Th1 to Th2 deviation) is attractive for several autoimmune diseases, such a mechanism for serial-combination therapy has never been formally demonstrated. Recently, brief mitoxantrone induction-chemotherapy followed by immune-modulation with glatiramer acetate (GA) was significantly more effective at reducing multiple sclerosis disease activity than with GA alone.


OBJECTIVE
To examine whether the benefit of initial immune suppression with mitoxantrone before GA treatment is associated with more efficient immune modulation.


METHODS
IgG1/IgG4 GA-reactive antibody profiles, previously established as markers of GA-induced Th2 immune-deviation, were prospectively measured in vivo in patients treated with GA alone or with mitoxantrone induction therapy followed by GA.


RESULTS
Significant and sustained increase in IgG4 antibodies (and the anticipated reversal of the IgG1/IgG4 ratio) was seen in patients treated with GA alone. Combination therapy resulted in lesser IgG4 induction (and no reversal of IgG1/IgG4 ratio). Thus, the enhanced efficacy of mitoxantrone-GA combination regimen was associated with decreased, rather than increased, efficiency of shifting the GA-reactive IgG1/IgG4 antibody profile.


CONCLUSIONS
These results provide important insights into mechanisms of combination therapy and therapeutic strategies for autoimmune diseases.
Bar-Or
A
A
Montreal Neurological Institute, Montreal, Quebec, Canada. amit.bar-or@mcgill.ca
Oger
J
J
Gibbs
E
E
Niino
M
M
Aziz
T
T
Renoux
C
C
Alatab
S
S
Shi
F D
FD
Campagnolo
D
D
Jalili
F
F
Rhodes
S
S
Yamashita
T
T
Fan
B
B
Freedman
M S
MS
Panitch
H
H
Arnold
D L
DL
Vollmer
T
T
D000293:Adolescent; D000328:Adult; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D000068717:Glatiramer Acetate; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000187:drug effects / Q000276:immunology; D007155:Immunologic Factors / Q000008:administration & dosage*; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone / Q000008:administration & dosage*; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology; D010455:Peptides / Q000008:administration & dosage*; D011446:Prospective Studies; D016037:Single-Blind Method; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D018418:Th2 Cells; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
D007074:Immunoglobulin G; D007155:Immunologic Factors; D007166:Immunosuppressive Agents; D010455:Peptides; D000068717:Glatiramer Acetate; D008942:Mitoxantrone