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1.
C Demanet J Brissinck M Van Mechelen O Leo K Thielemans 《Journal of immunology (Baltimore, Md. : 1950)》1991,147(3):1091-1097
It has previously been reported that T lymphocytes can be targeted by using bispecific antibodies consisting of anti-target antibody and anti-CD3. In the present study, a bispecific mAb was developed by somatic hybridization of mouse hybridomas, one producing a mAb against the Id determinant of the mouse B cell lymphoma 38C13 and the other a mAb against a polymorphic determinant on murine CD3. The bispecific antibody, anti-38C13 x anti-CD3, is bi-isotypic (IgG1 x IgG2a) and was purified by ion exchange and affinity chromatography. The dual specificity of the hybrid hybridoma-produced mAb could be demonstrated by flow cytometry, the induction of T cell proliferation, the induction of IL-2 secretion by polyclonal T cells, and redirected lysis of the relevant target cells. The hybrid (bi-isotypic) Fc part of the bispecific antibodies was nonfunctional in FcR-dependent redirected lysis. In vivo studies demonstrate that this bispecific mAb could efficiently target T cells towards the tumor cells, resulting in long term survival and cure of the lymphoma. 相似文献
2.
Busman-Sahay K Sargent E Harton JA Drake JR 《Journal of immunology (Baltimore, Md. : 1950)》2011,186(12):6710-6717
Previous work established that binding of the 11-5.2 anti-I-A(k) mAb, which recognizes the Ia.2 epitope on I-A(k) class II molecules, elicits MHC class II signaling, whereas binding of two other anti-I-A(k) mAbs that recognize the Ia.17 epitope fail to elicit signaling. Using a biochemical approach, we establish that the Ia.2 epitope recognized by the widely used 11-5.2 mAb defines a subset of cell surface I-A(k) molecules predominantly found within membrane lipid rafts. Functional studies demonstrate that the Ia.2-bearing subset of I-A(k) class II molecules is critically necessary for effective B cell-T cell interactions, especially at low Ag doses, a finding consistent with published studies on the role of raft-resident class II molecules in CD4 T cell activation. Interestingly, B cells expressing recombinant I-A(k) class II molecules possessing a β-chain-tethered hen egg lysosome peptide lack the Ia.2 epitope and fail to partition into lipid rafts. Moreover, cells expressing Ia.2(-) tethered peptide-class II molecules are severely impaired in their ability to present both tethered peptide or peptide derived from exogenous Ag to CD4 T cells. These results establish the Ia.2 epitope as defining a lipid raft-resident MHC class II conformer vital to the initiation of MHC class II-restricted B cell-T cell interactions. 相似文献
3.
Intrathymic, Ia-bearing antigen-presenting cells (APC) are believed to play an important role in the development of a mature, functional T-cell repertoire. We used chronic in vivo treatment of neonatal mice with anti-I-A monoclonal Ab (MAb) to examine the expression of I-A and I-E antigens on intrathymic and peripheral APC. Three weeks after continuous treatment with anti-I-A MAb, FACS analysis of unfractionated spleen cells revealed a 75-90% reduction in the number of I-A bearing cells. Splenic antigen-presenting capacity measured by the ability of unseparated or density gradient-enriched APC to stimulate I-A- or I-E-reactive T-cell hybridomas was also greatly reduced. In contrast to the expression of I-A and I-E molecules in the splenic APC, anti-I-A MAb treatment resulted in decreased thymic APC I-A expression without significant changes in I-E as measured by FACS analysis. This was confirmed in functional studies in which allo-I-A- or auto-I-A-reactive T-cell hybridomas could not be stimulated by treated thymic APC. Unlike splenic APC, anti-I-A-treated thymic APC did not differ significantly from normals in their ability to stimulate allo-I-E-reactive T hybridomas. This lack of linkage or comodulation of I-A and I-E expression on thymic but not splenic APC may allow us to study the role of I-A molecules and I-E molecules on the development and expansion of functional, mature T-cell repertoires. 相似文献
4.
Induction of proliferation of human follicular (B type) lymphoma cells by cognate interaction with CD4+ T cell clones 总被引:9,自引:0,他引:9
D T Umetsu L Esserman T A Donlon R H DeKruyff R Levy 《Journal of immunology (Baltimore, Md. : 1950)》1990,144(7):2550-2557
We examined stimuli which are required for the induction of in vitro proliferation of follicular lymphoma cells, a low grade non-Hodgkin's B cell lymphoma characterized by a specific chromosomal translocation, t(14;18)(q32;q21), and by in vivo growth of the lymphoma cells in germinal center-like follicles infiltrated with CD4+ T cells. The purified follicular lymphoma cells, which are morphologically uniform, small, and dense, did not respond to stimulation with soluble lymphokines in the absence of T cells. Vigorous in vitro proliferation of follicular lymphoma cells was induced, however, when the follicular lymphoma cells were cultured with a CD4+ T cell clone which recognized alloantigens expressed by the lymphoma cells. This response required B-T cell contact, and was inhibited by anti-class II but not by anti-class I MHC mAb, indicating that these neoplastic B cells behaved as normal B cells and responded to normal activation and differentiation signals from T cells. After the cognate B lymphoma-T cell interaction occurred in culture, addition of IL-2 or IL-4 enhanced the proliferation of the tumor cells. These results, with a monoclonal and homogeneous population of B cells, affirm the idea that cognate interaction between B cells and Th cells is required for the effective activation of resting B cells. Moreover, these results suggest that a critical host-tumor interaction occurs in vivo, and that the polyclonal CD4+ T cells that infiltrate follicular lymphomas play a role in sustaining rather than inhibiting tumor growth in vivo. If so, therapies directed not only against the neoplastic cell but also against specific T cells and their cognate interactions with tumor cells may have a rationale. 相似文献
5.
W Aberer A M Kruisbeek S Shimada S I Katz 《Journal of immunology (Baltimore, Md. : 1950)》1986,136(3):830-836
The in vivo activation of T cells by a variety of antigens can be inhibited by the administration of anti-I-A antibodies (Ab) at the time of antigen priming. This inhibition can partially be explained by the temporary loss of Ia molecules from Ia-bearing antigen-presenting cells (APC) in the spleen. In this study, the effects of i.p. injected monoclonal Ab specific for I-A glycoproteins of different H-2 haplotypes on Ia antigen expression and APC function of spleen cells and epidermal Langerhans cells were compared. It was found that anti-I-A Ab quickly bound to both spleen cell and Langerhans cell Ia antigens. Although spleen cell Ia antigens were modulated and thus temporarily disappeared, Ia antigen expression by epidermal Langerhans cells was not modulated. In functional studies, the capacity of spleen cells and epidermal cells from anti-I-A Ab treated vs control animals to function as APC for antigen-specific, I-A- or I-E-restricted T cell clones was tested. A single injection of anti-I-A Ab completely abolished the APC function of spleen cells as shown in several inbred mouse strains, F1 animals, and with the use of several different Ab and T cell clones. In contrast, Langerhans cell-dependent APC function of epidermal cells remained completely unaltered. Even multiple injections of high doses of Ab never caused any inhibition of Langerhans cell function. Experiments with anti-I-Ak or anti-I-Ad Ab in an (H-2k X H-2d)F1 animal showed abrogation of APC function of spleen cells, but again not of Langerhans cells. Thus in vivo anti-I-A Ab administration appears to differentially affect Ia antigen expression and APC function from spleen and epidermis: Ia antigens are modulated from spleen cells but not from epidermis, and APC function disappears in the spleen but not in the epidermis. The abrogation of splenic but not of Langerhans cell APC function with anti-I-A Ab will facilitate the dissection of the relative contributions of Langerhans cells as compared with other APC in the generation of cutaneous immune responses. 相似文献
6.
Spontaneously arising reticulum cell sarcoma (RCS) tumors in SJL/J mice stimulate syngeneic host T lymphocytes to proliferate and are dependent on host T cells for maintenance and growth. Tumor-associated Ia antigens have been implicated in the proliferative response both in vivo and in vitro, and the responding T cells are predominantly Lyt-1+2- L3T4+. We hypothesized that elimination or depletion of the responding L3T4 subpopulation in vivo should inhibit growth of transplantable RCS tumors, and continued RCS growth may be dependent on the continued presence of L3T4 cells. This hypothesis was tested experimentally by examining the effect of passive administration of L3T4 monoclonal antibody (mAb) into SJL/J mice either before or at different times after tumor inoculation. The tumor inoculum used killed all mice 15 to 30 days after injection. Administration of a single dose of L3T4 mAb 4 days before tumor inoculation resulted in complete depletion of L3T4 cells and complete inhibition of tumor growth. The antibody-treated mice survived with no sign of tumor growth even after complete recovery of L3T4+ cells. These results demonstrate that initiation of tumor growth is dependent on host L3T4+ cells. Administration of mAb as late as 7 days after tumor inoculation resulted in inhibition of tumor growth, and administration of mAb at day 10 resulted in significant inhibition of tumor growth. Compared with the kinetics of tumor growth in normal control mice, administration of L3T4 after tumor inoculation results in tumor growth arrest. These findings demonstrate that continued tumor growth in vivo is dependent on the presence of L3T4+ cells. In the RCS system, the present studies show that administration of mAb to L3T4+ cells is therapeutic in that it inhibits the induction of tumor growth, and it also prevents tumor growth in tumor-bearing animals. 相似文献
7.
T cells express MHC class II glycoproteins under various conditions of activation or inflammation. To assess whether T cell APC (T-APC) activity had long-term tolerogenic consequences, myelin basic protein (MBP)-specific rat T cells were induced to acquire MBP-derived I-A complexes to promote reciprocal antigen presentation. T-T antigen presentation caused extensive cell death among T-APC and MBP-specific T responders and caused long-term desensitization of surviving responders. Addition of the anti-I-A mAb OX6 to activated I-A+ responders inhibited T-APC activity, accelerated recovery from postactivation refractoriness, and prevented long-term loss of reactivity in responder T cells. Antigenic activation of responder T cells with irradiated T-APC induced profound losses in reactivity that lasted for over 1 month of propagation in IL-2 and was associated with preferential outgrowth of CD4- T cells. Antigen-activated CD4- T cells exhibited more rapid IL-2-dependent growth that eventually normalized compared to CD4+ T cells 1-2 months after antigen exposure. In conclusion, expression of T-APC activity by activated T cells represents an important negative feedback pathway that depletes antigen-reactive T cells and causes long-term desensitization of surviving T cells. Hence, T cell APC may be an important mechanism of self-tolerance. 相似文献
8.
N Haran-Ghera A Peled B K Brightman H Fan 《Journal of immunology (Baltimore, Md. : 1950)》1992,148(9):2947-2952
AKR mice are highly susceptible to spontaneous T cell lymphomagenesis and thymus removal at the age of 1 to 3 mo greatly reduces its development. Twelve-mo-old AKR mice thymectomized at young age were shown previously to carry potential lymphoma cells that could be triggered to develop into B cell lymphomas (80 to 100%) after removal from their host "restrictive" environment into young histocompatible hosts. Additional attempts were made to terminate the potential lymphoma cell dormant state in 12-mo-old thymectomized AKR mice. Replenishment of some deficiencies caused by thymectomy at a young age, including a s.c. syngeneic thymus graft or a single injection of the dual tropic recombinant virus isolates DTV-71 or MCF-247 into 12-mo-old thymectomized AKR mice resulted in Ly-1+ pre-B or B cell lymphoma development in 80 to 98% of these treated mice. In vivo elimination of T cell subsets by administration of cyclosporin A or by mAb expressed on Th cells (anti-CD4) or cytotoxic T cells (anti-CD8) stimulated the progression of dormant potential lymphoma cells towards B cell lymphoma development. The most striking results were observed after administration of anti-CD8 mAb: 90 to 100% of these treated mice developed Ly-1+ B cell lymphomas within 80 days. The effect of rIL-2 on dormant PLC was also tested. Administration of rIL-2 to 12-mo-old thymectomized mice terminated tumor dormancy in 94% of the treated mice within 66 days. Tests of the resulting B lymphomas for dual tropic recombinant virus/mink cell focus-inducing virus infection indicated that the breakdown of tumor dormancy did not result from development of pathogenic class I mink cell focus-inducing viruses. These results suggest that T cell subsets and/or their products are involved in the proliferation arrest of potential lymphoma cells present in thymectomized AKR mice. 相似文献
9.
Anti-I-A mAb were used as probes of functional epitopes for both the presentation of hen egg lysozyme (HEL) peptides to I-Ak-restricted T cell hybridomas and the direct binding of the HEL (46-61) peptide. When mAb directed to polymorphic regions of I-Ak were used as inhibitors of Ag presentation, several different patterns of inhibition were observed among T cells specific for the same HEL peptide as well as among T cells specific for different fragments of HEL. Although there appears to be a conserved usage of some TCR V beta gene segments among the T cell hybrids specific for the same HEL peptide, no correlation is evident between a single V gene usage and susceptibility to blocking of Ag presentation by a particular anti-I-Ak mAb. Several of the mAb demonstrated T cell "clonotypic blocking" of Ag presentation, whereas others blocked presentation to every T cell hybrid tested, regardless of the peptide specificity. When mAb directed to nonpolymorphic regions of the I-A molecule were tested for their ability to block Ag presentation, little or no inhibition was observed. In addition, Fab' fragments of inhibitory mAb functioned identically to their intact homologous counterparts in their ability to block Ag presentation indicating that "nonspecific" steric hindrance was not playing a major role in the inhibitions observed. When the polymorphic region-directed anti-I-A mAb were tested for their ability to block the direct binding of the lysozyme peptide HEL(46-61) to I-Ak, those mAb that block HEL presentation to all T cell hybrids were found to block the binding of this peptide. However, anti-I-A mAb that demonstrate selective inhibition of T cell hybrid stimulation during Ag presentation, i.e., those directed to polymorphic serologic specificities Ia.15 and Ia.19, do not block the binding of HEL(46-61) to I-Ak. These data indicate that functionally independent epitopes exist on the I-Ak molecule for the binding of antigenic peptides and for interaction with the TCR. 相似文献
10.
A M Kruisbeek J A Titus D A Stephany B L Gause D L Longo 《Journal of immunology (Baltimore, Md. : 1950)》1985,134(6):3605-3614
A single injection of anti-I-Ak antibody (AB) into H-2k mice resulted in abrogation of splenic antigen-presenting cell (APC) function for protein antigen-primed T cells or alloantigen-specific T cells. Spleen cells from anti-I-A-treated mice are not inhibitory in cell mixing experiments when using cloned antigen-specific T cells as indicator cells, thus excluding a role for suppressor cells in the observed defect. Also, nonspecific toxic effects and carry-over of blocking Ab were excluded as causes for the defect. Experiments with anti-I-Ak Ab in (H-2b X H-2k)F1 mice showed abrogation of APC function for T cells specific for both parental I-A haplotypes. In homozygous H-2k mice, anti-I-Ak treatment not only abrogated APC function for I-Ak-restricted cloned T cells but also for I-AekE alpha k-restricted cloned T cells. FACS analysis of spleen cells from anti-I-Ak-treated (H-2b X H-2k)F1 mice revealed the disappearance of all Ia antigens (both I-A and I-E determined), whereas the number of IgM-bearing cells was unaffected. The reappearance of APC function with time after injection was correlated with the reappearance of I-A and I-E antigen expression. In vitro incubation of spleen cells from anti-I-A-treated mice led to the reappearance of Ia antigen expression and APC function within 8 hr. Thus, it appears that B cells (as determined by FACS analysis) and APC (as determined by functional analysis) behave similarly in response to in vivo anti-I-A Ab treatment. We interpret these findings as suggesting that in vivo anti-I-A treatment temporarily reduces the expression of Ia molecules through co-modulation on all Ia-bearing spleen cells, thereby rendering them incompetent as APC. Such modulation of Ia molecules does not occur when spleen cells are incubated in vitro with anti-I-A antibodies. These results imply that a primary defect purely at the level of APC in anti-I-A-treated mice may be responsible for the observed T cell nonresponsiveness when such mice are subsequently primed with antigen. 相似文献
11.
Injection of a hybridoma anti-Ia antibody into adult mice results in a dramatic reduction in the expression of B cell sIa without affecting the expression of sIgD or sIgM. This anti-Ia-mediated modulation of B cell sIa occurs within 3 hr and attains it maximum effect within 18 hr after injection of antibody. There is a rapid reexpression of B cell Ia when such sIa- B cells are cultured in vitro. Culture of B cells in vitro with anti-Ia antibody has no discernible effect on the expression of B cell sIa, nor does it prevent the reexpression of sIa on sIa- B cells obtained from anti-Ia-injected mice. Injection of anti-I-A antibody suppresses the expression of both I-A and of I-E, and similarly, injection of anti-I-E suppresses the expression of B cell I-E and I-A antigens. When fluorescein-labeled monoclonal anti-I-A antibody is injected into mice, a significant fraction of B cell sIa can be demonstrated to be internalized by the B cell. The potential immunologic significance of this phenomena of anti-Ia-mediated modulation of B cell sIa is discussed. 相似文献
12.
Cochlovius B Kipriyanov SM Stassar MJ Christ O Schuhmacher J Strauss G Moldenhauer G Little M 《Journal of immunology (Baltimore, Md. : 1950)》2000,165(2):888-895
The use of anti-CD3 x antitumor bispecific Abs is an attractive and highly specific approach in cancer therapy. Recombinant Ab technology now provides powerful tools to enhance the potency of such immunotherapeutic constructs. We designed a heterodimeric diabody specific for human CD19 on B cells and CD3epsilon chain of the TCR complex. After production in Escherichia coli and purification, we analyzed its affinity, stability, and pharmacokinetics, and tested its capacity to stimulate T cell proliferation and mediate in vitro lysis of CD19+ tumor cells. The effect of the diabody on tumor growth was investigated in an in vivo model using immunodeficient mice bearing a human B cell lymphoma. The CD3 x CD19 diabody specifically interacted with both CD3- and CD19-positive cells, was able to stimulate T cell proliferation in the presence of tumor cells, and induced the lysis of CD19+ cells in the presence of activated human PBL. The lytic potential of the diabody was enhanced in the presence of an anti-CD28 mAb. In vivo experiments indicated a higher stability and longer blood retention of diabodies compared with single chain Fv fragments. Treatment of immunodeficient mice bearing B lymphoma xenografts with the diabody and preactivated human PBL efficiently inhibited tumor growth. The survival time was further prolonged by including the anti-CD28 mAb. The CD3 x CD19 diabody is a powerful tool that should facilitate the immunotherapy of minimal residual disease in patients with B cell leukemias and malignant lymphomas. 相似文献
13.
N Miki M Hatano K Wakita S Imoto S Nishikawa S Nishikawa T Tokuhisa 《Journal of immunology (Baltimore, Md. : 1950)》1992,149(3):801-807
The role of the Ia molecule in the early phase of B cell development remains controversial. In contrast to previous studies, we have detected minute amounts of Ia (I-A) molecule on early B lineage (B220+IgM-) cells from normal bone marrow, using ELISA. The presence of the I-A molecule even on pro-B cells was deduced from experiments in which a monoclonal anti-I-A antibody completely blocked the generation of pre-B cells from B progenitor (B220-) cells in stromal cell-dependent B cell culture. Inasmuch as this antibody did not inhibit the maturation of pre-B cells to IgM+ B cells in culture, the I-A molecule on early B lineage cells probably plays a role in their maturation. We also examined the role of the I-A molecule in early B cell development, using transgenic mice harboring the antisense DNA to I-A beta-chain gene. The amount of I-A molecule on splenic B cells from the young transgenic mice decreased in the presence of abundant amounts of the antisense RNA. B cell development was perturbed in spleen from the transgenic mice. Stromal cell-dependent B cell cultures from these mice clearly showed that the maturation of B lineage cells was delayed at a very early stage of development (B220- to B220+). We propose that the I-A molecule on early B lineage cells may play an essential role in their maturation. 相似文献
14.
T-helper-cell-specific monoclonal antibody inhibits growth of B-cell lymphomas in syngeneic SJL/J mice 总被引:1,自引:0,他引:1
Transplantable follicular center cell lymphomas of SJL/J mice are B-cell tumors that stimulate proliferation of host T-helper (TH) cells and which grow progressively in the peripheral lymphoid tissues of immunocompetent recipients. However, tumor growth is compromised in immunosuppressed syngeneic recipients, suggesting that the host response to SJL follicular center cell (SJL/FCC) lymphoma cells is required for optimal tumor growth. In vitro studies indicate that the host TH cells (Lyt-1+, 2-, L3T4a+) which respond to the major histocompatibility complex (MHC) class II (I-As) surface determinants on the SJL/FCC lymphoma cells produce a variety of lymphokines, some of which may promote tumor growth in vivo. The results of this study demonstrate that treatment of lymphoma-injected mice with L3T4a-specific mAb inhibits the growth of the SJL/FCC lymphoma cells, despite the fact that these tumor cells do not express L3T4a determinants. Thus, in this model, mAb therapy targeting host immune cells rather than the tumor cells is an effective means to control tumor growth. Long-term observation of SJL/FCC lymphoma-injected, anti-L3T4a mAb-treated mice reveals prolonged survival of the majority of these animals with periodic recurrence of tumor growth. During periods of remission, LN cells from these long-term surviving animals were unable to mount the characteristic in vitro host response to irradiated SJL/FCC lymphoma cells. These results provide direct evidence that SJL/FCC lymphoma cells fail to retain their characteristic neoplastic properties in a microenvironment that is initially devoid of tumor-responsive TH cells. 相似文献
15.
The T suppressor efferent circuit in the picryl (TNP) system, which inhibits the passive transfer of contact sensitivity, involves at least two antigen-nonspecific factors. The second nonspecific T suppressor factor (ns-2) bears I-A determinants of both the alpha and the beta chain as shown by affinity chromatography on immobilized anti-I-A monoclonal antibodies. Sequential absorption shows that the determinants of the alpha and beta chain occur on the same molecular complex. No absorption was obtained with anti-I-E antibody. There are two genetic restrictions associated with ns-2--the first is in its release from the second T suppressor efferent cell (on exposure to antigen) and the second is in its inhibitory interaction with its target cell. Both are MHC restricted and matching in I-A (but not I-E, or I-J) is sufficient. The question was asked whether the I-A of the ns-2 was directly responsible for the I-A genetic restriction in its action. F1 TsF was made in (H-2k X H-2b)F1 mice by injecting picrylated parental cells intravenously and triggering the release of ns-2 with the corresponding picrylated parental cells. Both I-Ak- and I-Ab-positive ns-2 were produced and were separated by affinity chromatography on immobilized anti-I-A monoclonal antibody. The I-A phenotype of these separated ns-2 of F1 origin determines the genetic restriction in their action; i.e., I-Ak+ ns-2 only inhibits passive transfer by H-2k cells and I-Ab+ ns-2 only acts on H-2b cells. In contrast, the I-A haplotype of the picrylated cell used to induce the Ts cell which makes ns-2 is unimportant. It was concluded that the I-A on the ns-2, and not a possible recognition site for I-A, serves as a restriction element. This finding suggests that ns-2 may act directly on the I-A-restricted T cell which mediates contact sensitivity. 相似文献
16.
L3T4 (CD4+) cells that mediate contact sensitivity to trinitrochlorobenzene express I-A determinants 总被引:5,自引:0,他引:5
The present study has further characterized the T cell-mediated inflammatory response of contact sensitivity (CS) to the hapten trinitrochlorobenzene (TNCB) in mice. A discernible CS response was found to be induced as early as 2 days after epicutaneous application of TNCB. The response peaked on Days 4 to 5 and it then declined to a nearly undetectable level by Days 10 to 11. Examination of the draining lymph nodes demonstrated that development of CS coincided with an increase in cellular proliferation and in the total number of cells present. Despite a severalfold increase in the cellular contents of the draining lymph nodes of sensitized mice, the relative percentages of most subsets of T cells remained unchanged. Flow cytometric studies revealed that the subpopulation of T cells characterized as Thy 1.2+ L3T4+ I-A+ increased substantially in comparison to its presence in unsensitized mice. Whether the Thy 1.2+ L3T4+ I-A+ cells that increased following sensitization represented the effector population that mediates CS was then examined. Four-day immune lymph node T cells or L3T4 cells positively selected from them were capable of adoptively transferring CS to normal mice. However, these cells, after treatment with anti-Ia antibody or anti-I-A monoclonal antibody and complement, were unable to transfer CS. These findings imply that expression of I-A determinants may indicate antigen-induced T cell activation in vivo and that L3T4 cells that mediate CS are I-A positive. 相似文献
17.
Induction of peripheral T cell anergy associated with stimulation through the TCR complex in vivo has been described in mice using chemically modified APC, staphylococcal enterotoxin B, and intact anti-CD3 mAb. In the latter two models, T cell proliferation, IL-2R expression, and lymphokine production have been demonstrated before subsequent induction of hyporesponsiveness, whereas in the former model, these events have not been observed. To further investigate the relationship between mitogenicity and induction of peripheral hyporesponsiveness, mice were treated with either mitogenic intact anti-CD3 mAb or nonmitogenic F(ab')2 fragments of anti-CD3 mAb. T cells from F(ab')2-treated mice demonstrated a selective decrease in helper functions, with minimal effect on CTL function. Specifically, a marked reduction in ability of Th cells to secrete IL-2 when challenged in vitro with mitogen or alloantigen was observed, which persisted for at least 2 mo after mAb administration and which was independent of T cell depletion. Proliferative function was decreased in CD4+ T cells and could not be fully restored with addition of exogenous IL-2. A helper defect was also evident in vivo, in that F(ab')2-treated mice were deficient in their ability to reject MHC-disparate skin grafts, and in vivo administration of IL-2 reconstituted their ability to reject skin grafts normally. In contrast, T cells from mice treated with intact mAb demonstrated a significant decrease in both CTL and helper functions. A long term reduction in TCR expression on CD4+ cells from F(ab')2-treated mice, and on both CD4+ and CD8+ cells from intact mAb-treated mice was observed. These findings demonstrate that peripheral T cell hyporesponsiveness can be induced in vivo by binding an identical epitope on the TCR complex in the presence or absence of initial proliferation, lymphokine secretion, or IL-2R expression, and that binding to the same epitope can result in varying long term effects on T cell function. 相似文献
18.
Anti-CD3 + IL-2-stimulated murine killer cells. In vitro generation and in vivo antitumor activity 总被引:3,自引:0,他引:3
P M Anderson B R Blazar F H Bach A C Ochoa 《Journal of immunology (Baltimore, Md. : 1950)》1989,142(4):1383-1394
The growth, phenotype, in vitro cytolytic characteristics, and in vivo antitumor activity of murine splenocytes stimulated with anti-murine CD3 mAb in combination with IL-2 as compared with IL-2 alone was investigated. When cultured for 12 days with anti-CD3 mAb + IL-2, murine splenocytes increased 100- to 4000-fold in number compared with only 6- to 20-fold for cultures stimulated with IL-2 alone. Anti-CD3 mAb + IL-2 activated cultures developed high lymphokine-activated killer activity against NK-resistant targets including the P815 mastocytoma cell line and fresh MCA 106 sarcoma. Peak cytotoxicity on a per cell basis developed by day 8 after anti-CD3 mAb + IL-2 activation. A large proportion of the total cytolytic activity of long term anti-CD3 mAb + IL-2-stimulated cultures was related to the presence of anti-CD3 in the assay, indicating enhancement of cytotoxicity by activated CD3+ T cells. Phenotypic analysis indicated that anti-CD3 mAb + IL-2-stimulated cultures contained heterogeneous populations of T cells with increased percentages of both CD4+ and CD8+ phenotypes compared with cultures stimulated with IL-2 alone. Anti-CD3 mAb + IL-2-stimulated cells were tested for their in vivo antitumor activity by using C57BL/6 mice bearing MCA 106 sarcoma pulmonary metastases. IL-2-activated murine killer cells were given in combination with in vivo IL-2 and indomethacin, the latter of which was shown to potentiate the antitumor effect of IL-2. When given on day 5 after tumor inoculation, cell doses as low as 5 x 10(6) anti-CD3 mAb + IL-2-stimulated cells per mouse significantly reduced the number of pulmonary metastases (p less than 0.005). Thus, activation with the combination of anti-CD3 mAb + IL-2 produces rapidly expanding cultures of cytolytic cells with demonstrated in vivo antitumor efficacy. 相似文献
19.
Immunoregulatory activities of autoreactive T cells: an I-A-specific T cell clone mediates both help and suppression of antibody responses 总被引:6,自引:0,他引:6
C Clayberger R H Dekruyff H Cantor 《Journal of immunology (Baltimore, Md. : 1950)》1984,132(5):2237-2243
We have derived a Ly-1+, 2-3- T cell clone that is specific for autologous I-A on activated but not on resting cells. After activation, this clone produces factors that induce purified (B + adherent) cells to secrete antibody in response to sheep red blood cells and type 2 T-independent antigens. Regulation of plaque-forming cell responses by this clone is dose dependent: low numbers enhance the plaque-forming cell response, whereas high numbers suppress the response. The inhibition observed with high doses is associated with cytolysis of I-A+ cells, and this can be blocked by the addition of anti-I-A antibodies. The physiologic significance of this novel cell type in regulating immune responses is discussed. 相似文献
20.
We have compared the functional properties of I-Ad expressed on different cell types. Specifically, we have transfected I-A alpha d and I-A beta d cDNA into a panel of T cell thymomas of various phenotypes. Excellent class II surface expression was achieved in all T cell tumors, equivalent in level to that found on the B cell lymphoma A20. Interestingly, however, two allo-I-Ad-specific Thy differed in their recognition of the transfected tumor cells: whereas the 42H11 T cell hybridoma (THy) was stimulated very efficiently by all transfectants, the RK38.2.2 Thy did not react to any of them. Both THy responded equally well to I-Ad on A20 B lymphoma cells. Purified macrophages isolated from various sources were also differentially recognized by the two THy, although there was only a quantitative difference in stimulation. Taken together, these results are best interpreted to show that the TCR of the RK38.2.2 THy is specific for I-Ad in the context of a B cell-specific determinant, possibly a self-peptide that is naturally associated with Ia. A cross-reactive molecule could be expressed by macrophages and COS-1 cells, but not by T cells. 相似文献