Purification to homogeneity and partial characterization of interleukin 2 from a human T-cell leukemia.

Three rat lymphoid cell lines (TARS-1, TARL-2, and TART-1) (12) transformed by human T cell leukemia/lymphoma virus I (HTLV-I) had rearrangement of the beta chain gene of the T cell antigen receptor, and had integrated proviral DNA from HTLV-I in their genomes. As is the case with adult T cell leukemia (ATL)-derived human T cell lines transformed by HTLV-I, these rat cell lines unequivocally expressed interleukin 2 (IL-2) receptor, as determined by radiolabeled IL-2 binding. By Scatchard plot analysis, one of the cell lines, TART-1, proved to have high affinity receptors (Ka = 1.3 X 10(11)/M and 8.8 X 10(9)/M). Rat IL-2 receptor, not human IL-2 receptor, was expressed on HTLV+ rat cell lines, as demonstrated by the fact that they expressed antigens reactive with monoclonal antibodies (ART-18) against rat IL-2 receptor, but not with anti-Tac antibodies. The collective evidence indicates that the endogenous IL-2 receptor gene is activated in human and rat lymphoid cell lines with HTLV-I production. The mechanism of abnormal IL-2 receptor expression in HTLV infection is discussed.

Download Full-text

The interleukin-2 receptor: a target for monoclonal antibody treatment of human T-cell lymphotrophic virus I-induced adult T-cell leukemia

Blood ◽

10.1182/blood.v82.6.1701.bloodjournal8261701 ◽

1993 ◽

Vol 82 (6) ◽

pp. 1701-1712 ◽

Cited By ~ 2

Author(s):

TA Waldmann ◽

JD White ◽

CK Goldman ◽

L Top ◽

A Grant ◽

...

Keyword(s):

Monoclonal Antibody ◽

T Cell ◽

Interleukin 2 ◽

Receptor Expression ◽

Rational Approach ◽

Resting Cells ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Adult T Cell Leukemia ◽

Human T Cell

Adult T-cell leukemia (ATL) is a malignancy of mature lymphocytes caused by the retrovirus human T-cell lymphotrophic virus-I (HTLV-I). It is an aggressive leukemia with an overall mortality rate of 50% within 5 months; no conventional chemotherapy regimen appears successful in inducing long-term disease-free survival in ATL patients. However, ATL cells constitutively express high-affinity interleukin-2 receptors (IL-2Rs) identified by the anti-Tac monoclonal antibody, whereas normal resting cells do not. To exploit this difference in receptor expression, we administered anti-Tac intravenously (IV) to 19 patients with ATL. In general the patients did not suffer untoward reactions, and in 18 of 19 cases did not have a reduction in normal formed elements of the blood. Seven patients developed remissions that were mixed (1 patient), partial (4 patients), or complete (2 patients), with partial and complete remissions lasting from 9 weeks to more than 3 years as assessed by routine hematologic tests, immunofluorescence analysis, and molecular genetic analysis of T-cell receptor gene rearrangements and of HTLV-I proviral integration. Furthermore, remission was associated with a return to normal serum calcium levels and an improvement of liver function tests. Remission was also associated in some cases with an amelioration of the profound immunodeficiency state that characterizes ATL. Thus the use of a monoclonal antibody that blocks the interaction of IL-2 with its receptor expressed on ATL cells provides a rational approach for treatment of this aggressive malignancy.

Download Full-text

A monoclonal antibody detecting a novel antigen expressed in the HTLV-I- infected cells

Blood ◽

10.1182/blood.v69.2.430.430 ◽

1987 ◽

Vol 69 (2) ◽

pp. 430-436 ◽

Cited By ~ 7

Author(s):

F Tsubai ◽

Y Namba ◽

M Kohno ◽

S Hanada ◽

M Matsumoto ◽

...

Keyword(s):

Monoclonal Antibody ◽

T Cell ◽

Cell Lines ◽

Polyacrylamide Gel Electrophoresis ◽

Sodium Dodecyl ◽

Interleukin 2 ◽

Lymphocytic Leukemia ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Human T Cell

Abstract A monoclonal antibody, FTF 148, was prepared by hybridizing murine myelomal cells (NS-1) and spleen cells of BALB/c mice immunized with cultured cells derived from an adult T cell leukemia (ATL) patient (KUT- 2 cells). This monoclonal antibody reacted with all of the human T cell leukemia virus I (HTLV-I)-infected cell lines tested but did not react with other T cell lines derived from acute lymphocytic leukemia, Epstein-Barr virus-transformed B cell lines, or an erythroleukemic cell line. This monoclonal antibody was not directed to viral antigens because it reacted equally well with almost all KUT-2 and MT-1 cells, only 1% to 3% of which were ATL-associated antigen-positive. In contrast to interleukin 2 receptors expressed on both ATL cells and normal phytohemagglutinin-stimulated blasts, this antigen was not expressed on the latter cells. The antigen, mainly expressed on the cell membrane, was analyzed by metabolic labeling with 3H-leucine and surface labeling with 125I followed by cell lysis and immunoprecipitation with the FTF 148 antibody. The findings obtained by sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed that p50 and p74 proteins were specifically precipitated and the antigen was also different from the product of the Xs gene of HTLV-I.

Download Full-text

Interleukin-2 increases production and secretion of parathyroid hormone-related peptide by human T cell leukemia virus type I-infected T cells: possible role in hypercalcemia associated with adult T cell leukemia.

Endocrinology ◽

10.1210/endo.132.6.8099324 ◽

1993 ◽

Vol 132 (6) ◽

pp. 2551-2556 ◽

Cited By ~ 16

Author(s):

K Ikeda ◽

R Okazaki ◽

D Inoue ◽

H Ohno ◽

E Ogata ◽

...

Keyword(s):

T Cell ◽

Leukemia Virus ◽

Interleukin 2 ◽

Type I ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Cell Leukemia Virus Type ◽

Adult T Cell Leukemia ◽

Human T Cell ◽

T Cell Leukemia Virus

Download Full-text

Expression and Characterization of Proteins Produced by mRNAs Spliced into the X Region of the Human T-Cell Leukemia/Lymphotropic Virus Type II

Virology ◽

10.1006/viro.1995.1277 ◽

1995 ◽

Vol 209 (2) ◽

pp. 445-456 ◽

Cited By ~ 41

Author(s):

Vincenzo Ciminale ◽

Donna M. D'Agostino ◽

Lorenza Zotti ◽

Genoveffa Franchini ◽

Barbara K. Felber ◽

...

Keyword(s):

T Cell ◽

Virus Type ◽

Type Ii ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Human T Cell

Download Full-text

Soluble interleukin 2 receptors in sera of Japanese patients with adult T cell leukemia mark activity of disease

Blood ◽

10.1182/blood.v71.4.1021.1021 ◽

1988 ◽

Vol 71 (4) ◽

pp. 1021-1026 ◽

Cited By ~ 65

Author(s):

N Yasuda ◽

PK Lai ◽

SH Ip ◽

PC Kung ◽

Y Hinuma ◽

...

Keyword(s):

T Cell ◽

Interleukin 2 ◽

Enzyme Linked Immunosorbent Assay ◽

Type I ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Normal Range ◽

Cell Leukemia Virus Type ◽

Adult T Cell Leukemia ◽

Human T Cell

Abstract Serum concentrations of soluble interleukin 2 receptors (sIL 2R) were measured by an enzyme-linked immunosorbent assay (ELISA) in 30 patients with adult T cell leukemia (ATL), in 9 patients with other hematopoietic malignancies, and in 17 asymptomatic individuals seropositive for human T cell leukemia virus type I (HTLV-I). Sixty HTLV-I seronegative, age-matched controls showed a normal range of form 63.2 to 480.8 U/mL. All asymptomatic carriers of HTLV-I had sIL 2R in their sera within the normal range. sIL 2R in sera was not related to the anti-HTLV-I antibody titer. Eleven patients with acute ATL, a clinical phenotype with median survival rate of 4.4 months, had markedly elevated sIL 2R (11,100 to 99,000 U/mL), but eight patients with smoldering ATL had low sIL 2R values (less than 480.8 U/mL) comparable to controls. Eleven patients with chronic ATL had intermediate elevated levels of sIL 2R (480.8 to 37,300.0 U/mL). Serum levels of sIL 2R correlated with the number of ATL cells (r = 0.812) and CD25-positive cells (r = 0.725) circulating in the peripheral blood. Longitudinal studies performed in four patients with ATL showed significant correlation between serum concentration of sIL 2R and activity of the malignancy. These findings suggest that the level of sIL 2R in serum indicated tumor load and, possibly, prognosis.

Download Full-text

Therapy of patients with human T-cell lymphotrophic virus I-induced adult T-cell leukemia with anti-Tac, a monoclonal antibody to the receptor for interleukin-2

Blood ◽

10.1182/blood.v72.5.1805.1805 ◽

1988 ◽

Vol 72 (5) ◽

pp. 1805-1816 ◽

Cited By ~ 111

Author(s):

TA Waldmann ◽

CK Goldman ◽

KF Bongiovanni ◽

SO Sharrow ◽

MP Davey ◽

...

Keyword(s):

Monoclonal Antibody ◽

T Cell ◽

Interleukin 2 ◽

Rational Approach ◽

Resting Cells ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Antitumor Effects ◽

Adult T Cell Leukemia ◽

Human T Cell

Abstract Human T-cell lymphotropic virus I (HTLV-I)-induced adult T-cell leukemia (ATL) cells constitutively express interleukin-2 (IL-2) receptors identified by the anti-Tac monoclonal antibody (MoAb), whereas normal resting cells do not. This observation provided the scientific basis for a trial of intravenous anti-Tac in the treatment of nine patients with ATL. The patients did not suffer untoward reactions and did not have a reduction in the normal formed elements of the blood, and only one of the nine produced antibodies to the anti-Tac MoAb. Three patients had transient mixed, partial, or complete remissions lasting from 1 to more than 8 months after anti-Tac therapy, as assessed by routine hematologic tests, immunofluorescence analysis of circulating cells, and molecular genetic analysis of HTLV-I provirus integration and of the T-cell receptor gene rearrangement. The precise mechanism of the antitumor effects is unclear; however, the use of a MoAb that prevents the interaction of IL-2 with its receptor on ATL cells provides a rational approach for the treatment of this malignancy.

Download Full-text

In vivo genetic mutations define predominant functions of the human T-cell leukemia/lymphoma virus p12I protein

Blood ◽

10.1182/blood-2008-04-146928 ◽

2009 ◽

Vol 113 (16) ◽

pp. 3726-3734 ◽

Cited By ~ 31

Author(s):

Risaku Fukumoto ◽

Vibeke Andresen ◽

Izabela Bialuk ◽

Valentina Cecchinato ◽

Jean-Claude Walser ◽

...

Keyword(s):

Amino Acid ◽

T Cell ◽

Cellular Localization ◽

Ex Vivo ◽

Interleukin 2 ◽

Proteolytic Cleavage ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Hydrophobic Membrane ◽

Human T Cell

AbstractThe human T-cell leukemia/lymphoma virus type 1 (HTLV-1) ORF-I encodes a 99–amino acid hydrophobic membrane protein, p12I, that affects receptors in different cellular compartments. We report here that proteolytic cleavage dictates different cellular localization and functions of p12I. The removal of a noncanonical endoplasmic reticulum (ER) retention/retrieval signal within the amino terminus of p12I is necessary for trafficking to the Golgi apparatus and generation of a completely cleaved 8-kDa protein. The 8-kDa protein in turn traffics to the cell surface, is recruited to the immunologic synapse following T-cell receptor (TCR) ligation, and down-regulates TCR proximal signaling. The uncleaved 12-kDa form of p12I resides in the ER and interacts with the β and γc chains of the interleukin-2 receptor (IL-2R), the heavy chain of the major histocompatibility complex (MHC) class I, as well as calreticulin and calnexin. Genetic analysis of ORF-I from ex vivo samples of HTLV-1–infected patients reveals predominant amino acid substitutions within ORF-I that affect proteolytic cleavage, suggesting that ER-associated functions of p12I may contribute to the survival and proliferation of the infected T cells in the host.

Download Full-text