TY - JOUR
T1 - Treatment with depleting CD4 monoclonal antibody results in a preferential loss of circulating naive T cells but does not affect IFN-γ secreting TH1 cells in humans
AU - Rep, Martin H.G.
AU - Van Oosten, Bob W.
AU - Roos, Marijke T.L.
AU - Adèr, Herman J.
AU - Polman, Chris H.
AU - Van Lier, René A.W.
PY - 1997/5/1
Y1 - 1997/5/1
N2 - CD4(pos) TH1 T cells are considered to play a central role in a number of human autoimmune diseases such as rheumatoid arthritis (RA) and multiple sclerosis. Experimental treatment protocols aimed at selectively eliminating CD4(pos) T cells thus far have yielded disappointing clinical results. Here we analyzed phenotype and function of circulating T cells in multiple sclerosis patients treated with the chimeric CD4 mAb cM-T412 in a randomized, double-blind, placebo-controlled, magnetic resonance imaging-monitored phase II trial. Treatment resulted in a long-lasting depletion of CD4(pos) T cells but did not affect CD8(pos) T cell numbers. Analysis of CD4(pos) subpopulations showed that unprimed, CD45RA(pos) R0(neg) lymphocytes were approximately three times more sensitive to the mAb than primed, CD45RA(neg)/R0(pos) T cells. Notably, within the CD45RA(pos) subset, T cells with phenotypic evidence of prior activation, i.e., expressing Fas, were relatively insensitive to cM-T412, compared with Fas(neg) cells. Remarkably, while a decrease in the number of IL-4-producing T helper 2 (TH2)-type cells in the anti-CD4 treated group was observed, numbers of IFN-γ-producing T helper 1 (TH1)-type cells remained stable, resulting in a significant increase in the TH1/TH2 ratio. Our data show that treatment with depleting CD4 mAb does not eliminate the cells most strongly involved in the disease process, i.e., primed, lFN-γ-producing TH1-type cells, and may therefore give an explanation for the lack of beneficial clinical effects of depleting CD4 mAb in human chronic autoimmune disease.
AB - CD4(pos) TH1 T cells are considered to play a central role in a number of human autoimmune diseases such as rheumatoid arthritis (RA) and multiple sclerosis. Experimental treatment protocols aimed at selectively eliminating CD4(pos) T cells thus far have yielded disappointing clinical results. Here we analyzed phenotype and function of circulating T cells in multiple sclerosis patients treated with the chimeric CD4 mAb cM-T412 in a randomized, double-blind, placebo-controlled, magnetic resonance imaging-monitored phase II trial. Treatment resulted in a long-lasting depletion of CD4(pos) T cells but did not affect CD8(pos) T cell numbers. Analysis of CD4(pos) subpopulations showed that unprimed, CD45RA(pos) R0(neg) lymphocytes were approximately three times more sensitive to the mAb than primed, CD45RA(neg)/R0(pos) T cells. Notably, within the CD45RA(pos) subset, T cells with phenotypic evidence of prior activation, i.e., expressing Fas, were relatively insensitive to cM-T412, compared with Fas(neg) cells. Remarkably, while a decrease in the number of IL-4-producing T helper 2 (TH2)-type cells in the anti-CD4 treated group was observed, numbers of IFN-γ-producing T helper 1 (TH1)-type cells remained stable, resulting in a significant increase in the TH1/TH2 ratio. Our data show that treatment with depleting CD4 mAb does not eliminate the cells most strongly involved in the disease process, i.e., primed, lFN-γ-producing TH1-type cells, and may therefore give an explanation for the lack of beneficial clinical effects of depleting CD4 mAb in human chronic autoimmune disease.
KW - autoimmune diseases therapy
KW - CD4 antibodies, monoclonal
KW - multiple sclerosis
KW - T lymphocyte subsets
KW - Thl cells
UR - http://www.scopus.com/inward/record.url?scp=0030926207&partnerID=8YFLogxK
U2 - 10.1172/JCI119396
DO - 10.1172/JCI119396
M3 - Article
C2 - 9151795
AN - SCOPUS:0030926207
VL - 99
SP - 2225
EP - 2231
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 9
ER -