Transactivation of interleukin 2 and its receptor induces immune activation in human T-cell lymphotropic virus type I-associated myelopathy: pathogenic implications and a rationale for immunotherapy.
A state of T-cell activation, reflected by a marked degree of spontaneous proliferation in vitro, exists among patients with human T-cell lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) but not in those with retroviral-induced adult T-cell leukemia (ATL). We wished to define the mechanism by which the immune activation of circulating cells from HAM/TSP is driven, thus gaining insight into the pathogenesis of this HTLV-I-associated disease. By using a modification of the polymerase chain reaction, we compared the levels of interleukin 2 (IL-2) and IL-2 receptor alpha chain (IL-2R alpha) mRNA expression to the transcription of the HTLV-I transactivator gene, pX, in peripheral blood mononuclear cells of HAM/TSP and ATL patients as well as seropositive carriers. Up-regulation of IL-2 and IL-2R alpha transcripts was detected in HAM/TSP and seropositive carriers that paralleled the coordinate mRNA expression of the pX transactivator. In addition, IL-2 and soluble IL-2R alpha serum levels in HAM/TSP and seropositive carriers were elevated. Despite markedly elevated levels of soluble IL-2R alpha in ATL, transcripts for IL-2 and pX were not demonstrable in the circulating cells. Finally, the marked degree of in vitro spontaneous proliferation present in HAM/TSP was profoundly inhibited by specific anti-IL-2R or anti-IL-2 blocking antibodies. Collectively, these results suggest that immune activation in HAM/TSP, in contrast to ATL, is virally driven by the transactivation and coordinate expression of IL-2 and IL-2R alpha. This deregulated autocrine process may contribute to the evolution of inflammatory nervous system damage in HAM/TSP.
Tendler
C L
CL
Metabolism Branche, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Greenberg
S J
SJ
Blattner
W A
WA
Manns
A
A
Murphy
E
E
Fleisher
T
T
Hanchard
B
B
Morgan
O
O
Burton
J D
JD
Nelson
D L
DL
D001483:Base Sequence; D015139:Blotting, Southern; D005260:Female; D015368:Human T-lymphotropic virus 1 / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007167:Immunotherapy; D007376:Interleukin-2 / Q000276:immunology*; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000276:immunology* / Q000628:therapy; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009693:Nucleic Acid Hybridization; D015345:Oligonucleotide Probes; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D015375:Receptors, Interleukin-2 / Q000276:immunology*; D012016:Reference Values; D015533:Transcriptional Activation
D007376:Interleukin-2; D015345:Oligonucleotide Probes; D012333:RNA, Messenger; D015375:Receptors, Interleukin-2