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PubMed1988

Immunohistochemical monitoring of metastatic colorectal carcinoma in patients treated with monoclonal antibodies (MAb 17-1A).

A therapeutic trial using repeated doses of a mouse monoclonal antibody against the tumor-associated antigen (TAA) CO17-1A in metastatic colorectal carcinomas was carried out. Metastatic lesions sampled by repeated thick needle (1.2 mm) biopsies during therapy were examined immunohistochemically for the presence of various TAAs, mouse IgG, complement, and infiltrating leukocytes. The CO17-1A was consistently expressed in all cases along the basement membrane of tumor glands and could only be demonstrated on cryostat sections whereas the TAAs GICA19-9, GA73-3, and Br55-2 were also visualized in B5-fixed paraffin-embedded biopsies. The CO17-1A and GA73-3 were predominantly present at the basal region in contrast to the GICA 19-9 and Br55-2 which were predominant at the luminal and the apical region of the tumor glands. Antigenic modulation was not seen either after 24-72 h or during prolonged treatment. In all cases the infused mouse IgG was detected, from 24 h after infusion up to 6-8 weeks, mainly along the basal region of tumor glands. In 13/14 posttreatment biopsies, complement factor C3 was found at the same sites as mouse IgG. In 6 out of 9 posttreatment biopsies an increase in mononuclear cells (monocytes, natural killer (NK) cells and/or T cells) was observed. Monocytes were close to the tumor cells whereas NK cells and T cells were predominantly scattered in the stroma.

Adult↗
PubMed1995

Flow cytometric monitoring of allergen induced basophil activation.

Human basophils express many clustered differentiation antigens (CD), including CD45; however, none are specific for these cells. In a previous study, we described a two-color immunofluorescence procedure, employing antibodies to CD45 and IgE for the cytometric evaluation of basophils. In the present work, we show that when sensitized basophils are stimulated by allergenic preparations, they demonstrate an upregulation of CD45 as well as a decrease in anti-IgE binding. Since CD45 antigen modulation was observed with all aeroallergens tested and the decrease in IgE expression varied with allergenic preparations, the measurement of CD45 upregulation was used to evaluate basophil activation. Using this approach, reproducible results were observed when atopic patients were tested at different time intervals. In addition, we show that the upregulation of CD45 on allergen stimulated basophils is a very rapid phenomenon that is observed after a few minutes and that this rapid flow cytometric method can also be used for investigations on nonallergenic mediators of basophil stimulation such as calcium ionophores.

Adult↗
PubMed1983

Human T lymphocyte proliferation induced by a pan-T monoclonal antibody (anti-Leu 4): heterogeneity of response is a function of monocytes.

Anti-Leu-4 is a murine monoclonal antibody that defines a molecule of 20,000 to 25,000 daltons present on all mature T lymphocytes in man. When cultured in the presence of 10 to 1000 ng/ml anti-Leu-4, the T cells of most individuals proliferate with peak responses on the third day of culture. T cells of both helper and suppressor lineages proliferate, but only in the presence of monocytes. Approximately 40% of individuals tested responded weakly or not at all to anti-Leu-4, despite normal responses to other stimuli. The variation in responsiveness between individuals could not be explained by differences in Leu-4 antigen density on the surface of T cells, differences in the rate of Leu-4 antigen modulation, or structural differences in the Leu-4 molecule as defined by the method of two-dimensional polyacrylamide gel electrophoresis. In the presence of monocytes from high responders, the T cells from low responders proliferated vigorously to anti-Leu-4, whereas monocytes from low responders failed to support proliferation by high responder T cells. On the other hand, low responder monocytes did not prevent T cells from proliferating in the presence of high responder monocytes. These results suggest that the failure of some individuals to respond to anti-Leu-4 is due to the absence or dysfunction of an essential monocyte population.

Adult↗
PubMed2005

Anti-CD23 monoclonal antibody, lumiliximab, inhibited allergen-induced responses in antigen-presenting cells and T cells from atopic subjects.

BACKGROUND: CD23 plays a role in the regulation of IgE production and allergy-induced immune and inflammatory responses. A novel anti-CD23 monoclonal antibody, lumiliximab, is a potential therapeutic antibody recently demonstrated to be safe in human beings. OBJECTIVE: This study investigated the effects of lumiliximab on allergen-induced immune responses from atopic subjects compared with blocking HLA-DR and costimulatory molecules, CD80 and CD86. METHODS: Allergen-stimulated PBMCs from atopic subjects were pretreated with lumiliximab or antibodies to CD80, CD86, and HLA-DR. Cultures were analyzed for cell proliferation and IL-1beta, TNF-alpha, and IL-5 cytokine secretion. An allergen-specific T-cell line was developed and analyzed for lymphocyte proliferation in response to allergen with or without lumiliximab. Lumiliximab's effect on CD86 expression was evaluated by flow cytometry in the U937 monocytic cell line. RESULTS: Lumiliximab reduced allergen-induced PBMC proliferation by 50% (n = 6; P = .006). In addition, cultures pretreated with lumiliximab had a reduction in the proinflammatory cytokines IL-1beta (P < .003) and TNF-alpha (P = .05) and the T(H)2 cytokine IL-5 (P = .002). Blocking CD86 resulted in greater reduction in proliferation than lumiliximab (P = .003) but similar effects in cytokine secretion. The anti-CD80 blocking antibody had no effect on cytokine production but did reduce proliferation. Furthermore, the addition of lumiliximab to cytokine stimulated U937 cells reduced surface expression of CD86 (P = .012). CONCLUSION: These results indicate that the anti-CD23 mAb, lumiliximab, may be involved in modulating antigen presenting cells and reducing TH2-type immune responses. The use of this antibody may provide clinical benefit for treating allergic diseases.

Allergens↗
PubMed2003

Archaeosomes varying in lipid composition differ in receptor-mediated endocytosis and differentially adjuvant immune responses to entrapped antigen.

Archaeosomes prepared from total polar lipids extracted from six archaeal species with divergent lipid compositions had the capacity to deliver antigen for presentation via both MHC class I and class II pathways. Lipid extracts from Halobacterium halobium and from Halococcus morrhuae strains 14039 and 16008 contained archaetidylglycerol methylphosphate and sulfated glycolipids rich in mannose residues, and lacked archaetidylserine, whereas the opposite was found in Methanobrevibacter smithii, Methanosarcina mazei and Methanococcus jannaschii. Annexin V labeling revealed a surface orientation of phosphoserine head groups in M. smithii, M. mazei and M. jannaschii archaeosomes. Uptake of rhodamine-labeled M. smithii or M. jannaschii archaeosomes by murine peritoneal macrophages was inhibited by unlabeled liposomes containing phosphatidylserine, by the sulfhydryl inhibitor N-ethylmaleimide, and by ATP depletion using azide plus fluoride, but not by H. halobium archaeosomes. In contrast, N-ethylmaleimide failed to inhibit uptake of the four other rhodamine-labeled archaeosome types, and azide plus fluoride did not inhibit uptake of H. halobium or H. morrhuae archaeosomes. These results suggest endocytosis of archaeosomes rich in surface-exposed phosphoserine head groups via a phosphatidylserine receptor, and energy-independent surface adsorption of certain other archaeosome composition classes. Lipid composition affected not only the endocytic mechanism, but also served to differentially modulate the activation of dendritic cells. The induction of IL-12 secretion from dendritic cells exposed to H. morrhuae 14039 archaeosomes was striking compared with cells exposed to archaeosomes from 16008. Thus, archaeosome types uniquely modulate antigen delivery and dendritic cell activation.

Adjuvants, Immunologic↗
PubMed1990

Activated human T lymphocytes express MHC class I heavy chains not associated with beta 2-microglobulin.

We present here the molecular characterization of a new activation-induced surface structure on human T lymphocytes, termed LA45, with high homology (93% at protein level) to MHC class I molecules. Antigen modulation and sequential immunoprecipitation experiments revealed that LA45 and HLA class I proteins do not crossreact with the corresponding antibodies. Furthermore, LA45 is not associated with beta 2-m. On the other hand, we could show that the separation of HLA-A,B,C and beta 2m molecules, induced by SDS-denaturation, leads to a conformational change in the heavy chain in such a way that it becomes reactive with LA45. The 90/45 kD LA45 proteins thus appear to be non-beta 2m-associated MHC class I alpha chains that are selectively expressed by activated but not by resting human T lymphocytes.

Amino Acid Sequence↗
PubMed1995

CD38 unresponsiveness of xid B cells implicates Bruton's tyrosine kinase (btk) as a regular of CD38 induced signal transduction.

CD38 is a 42 kDa membrane-associated ectoenzyme expressed by a large proportion of human and mouse lymphocytes. Agonistic antibodies to CD38 induce a strong proliferative response in lymphocytes additionally co-stimulated with other growth co-factors such as IL-4, IL-2 plus accessory cells or sub-mitogenic doses of endotoxin. We show here that B lymphocytes from unstimulated X-linked immunodeficient (xid) mice are unresponsive to CD38 stimulation, both in terms of proliferative response and surface antigen modulation. This CD38 unresponsiveness is evident in the presence of excess quantities of, and normal responses to, the accessory growth co-stimulants required for this response. CD38 molecules expressed on xid B cells are normal in terms of expression levels, size and enzymatic activity, suggesting that CD38 unresponsiveness reflects a down-stream signaling defect. In light of the recent proposal that the xid gene encodes a tyrosine kinase called Bruton's tyrosine kinase (btk), these data suggest that btk is either an integral component or an indirect regulator of the CD38-induced signal transduction pathway.

ADP-ribosyl Cyclase↗
PubMed1983

Granulocytes and cultured human fibroblasts express common acute lymphoblastic leukemia-associated antigens.

We have investigated the expression of the common acute lymphoblastic leukemia antigen (cALLA) by nonlymphoid cells, using a new murine monoclonal antibody (designated 24.1), specific for cALLA. This antibody completely blocks the binding of monoclonal anti-cALLA antibody J-5. Furthermore, antibody 24.1 binds to cALLA with greater affinity and induces a greater degree of antigenic modulation than antibody J-5. With antibody 24.1, we have demonstrated that normal cultured marrow and skin fibroblasts and mature granulocytes express cALLA. By immune precipitation and polyacrylamide gel electrophoresis, cALLA from fibroblasts has a slightly lower molecular weight and cALLA from granulocytes a slightly higher molecular weight than cALLA from cultured human leukemic cell lines. Quantitative studies indicate, however, that cALLA expression is approximately 3-fold and 20-fold lower, respectively, on normal granulocytes and skin fibroblasts than on NALM-6 cells. cALLA may be expressed by cells with widespread distribution in multiple organ systems. These findings emphasize that differentiation markers that appear to be tumor or tissue specific may be found on cells of diverse origin.

Animals↗
PubMed1998

Phase I study of the pharmacokinetics of a radioimmunoconjugate, 90Y-T101, in patients with CD5-expressing leukemia and lymphoma.

Ten patients with advanced or refractory CD5-expressing hematologic neoplasms [two with chronic lymphocytic leukemia and eight with cutaneous T-cell lymphoma (CTCL)] were treated in a Phase I study with the radioimmunoconjugate 90Y-T101, which targets CD5+ lymphocytes. Prior imaging studies using 111In-T101 demonstrated uptake in involved lymph nodes and skin in patients with CTCL, and Phase I studies with unmodified T101 demonstrated transient responses. In this study, patients were treated with 5 or 10 mCi of 90Y chelated to T101 via isothiocyanatobenzyl diethylenetriamine pentaacetic acid, along with tracer doses of 111In-T101 for imaging. The biodistribution of the radioimmunoconjugate was determined by measuring 90Y and 111In blood clearance, urine excretion, and accumulation in bone marrow and in involved skin lesions. The intravascular pharmacokinetics of 90Y were predicted by 111In-labeled T101. The greatest differences in biodistribution between 111In and 90Y were in the higher bone accumulation of 90Y and its lower urinary excretion. Imaging studies demonstrated targeting of skin lesions and involved lymph nodes in CTCL patients. The predominant toxicity was bone marrow suppression. Rapid antigenic modulation of CD5 on circulating T and B cells was observed. Recovery of T-cell populations occurred within 2-3 weeks; however, suppression of B-cell populations persisted after 5+ weeks. All CTCL patients developed human antimouse antibody after one cycle and thus were not retreated; one patient with chronic lymphocytic leukemia received a second cycle of therapy. Partial responses occurred in five patients, two with chronic lymphocytic leukemia and three with CTCL. The median response duration was 23 weeks. One CTCL patient who subsequently received electron beam irradiation to a residual lesion is disease-free after 6 years.

Adult↗
PubMed1987

A novel 90-kDa polypeptide (Tp90) possibly involved in an antigen-independent pathway of T cell activation.

A novel surface molecule, Tp90, is described which appears to be involved in an antigen-independent pathway of human T lymphocyte activation. The Tp90 molecule was identified by a monoclonal antibody (mAb), MX20, obtained from a fusion using spleen cells of a mouse immunized with cells from two T cell leukemia lines, Jurkat and HPB-ALL. Biochemical data show that Tp90 is distinct and physically independent from the structures already known to be involved in T cell activation, namely T11, T44 or T3/TCR. These results were confirmed by antibody-induced antigen modulation experiments. Modulation of Tp90 had no effect on the expression of T3 and of the T cell receptor. Conversely, the expression of Tp90 was not affected by modulation of the T3/TCR molecular complex by either anti-T3 or anti-TCR antibody. Functional studies showed that anti-Tp90 mAb MX20 induced high levels of interleukin 2 production in Jurkat cells. Modulation of the T3/TCR complex significantly decreased the response of Jurkat cells to stimulation by antibody MX20, suggesting that the T3/TCR complex regulates the ability of the Tp90 molecule to induce IL 2 synthesis. In addition to its effect on Jurkat cells, anti-Tp90 mAb was found to be mitogenic for peripheral blood T cells. As the magnitude of the proliferative response elicited by anti-Tp90 mAb was lower than that induced by anti-T3 mAb, the possibility was considered that only a subpopulation of T cells is reactive with anti-Tp90. Indeed as determined by FACS analyses, only 3-14% of E-rosette-positive cells were stained with mAb MX20. In addition, multicolor flow cytometry analysis showed that the Tp90+ cells belong preferentially to the CD8 subset.

Antibodies, Monoclonal↗
PubMed1993

Antibody-mediated redistribution and shedding of endothelial antigens in the rabbit.

We report the results of studies performed in vitro and in vivo that were designed to explore individual, sequential, and concurrent Ag-antibody interactions at the surface of rabbit endothelial cells. Divalent heterologous antibodies to rabbit lung angiotensin-converting enzyme and to rabbit lung thrombomodulin were employed. In cultured monolayers, both antibodies redistributed the specific Ag and co-redistributed the immunologically unrelated Ag inducing partial or complete disappearance of the Ag from the cell surface (antigenic modulation) in 15 to 60 min. When injected into living rabbits, each antibody induced a rapid (1 to 3 min) redistribution and subsequent modulation of the specific and of the unrelated Ag at the surface of alveolar endothelial cells. Immune complexes, and the unrelated Ag, were shed in the circulation, attaining peak levels 3 to 4 min after the injection; were rapidly bound by platelets, E, and polymorphonuclear leukocytes; and were subsequently found in phagocytic cells in the spleen and in the liver. Thrombomodulin co-shed by angiotensin-converting enzyme antibody and, to a lesser degree, angiotensin-converting enzyme co-shed by thrombomodulin antibody, crossed the glomerular capillary walls and were reabsorbed by the epithelial cells of the proximal tubules within 2 to 3 min. The results show that immunologically unrelated Ag can be passively entrapped during formation of immune complexes at the cell surface, and provide new information on the kinetics of clearance of immune complexes containing endogenous, structural Ag.

Animals↗
PubMed1983

Identification and functional characterization of two distinct epitopes on the human T cell surface protein Tp50.

The structural and functional domains of Tp50, the human T lymphocyte surface protein associated with the E rosette receptor, were probed with the use of two murine monoclonal antibodies. Lysostripping, immune precipitation, and competitive binding experiments demonstrated that antibodies 9.6 and 35.1 bind to Tp50 epitopes in close proximity. In functional studies, both antibodies caused a similar degree of antigenic modulation, inhibited T cell proliferative responses, and inhibited cytotoxic T lymphocyte function without affecting cells that mediate antibody-dependent cell-mediated cytotoxicity. The antibodies were strikingly different, however, in that antibody 9.6 inhibited E rosette formation and natural killer cell-mediated lysis, whereas antibody 35.1 did not. These results could not be ascribed to differences in antibody class or binding characteristics, because Scatchard analysis demonstrated that these two IgG2a antibodies have comparable avidity and that T cells bind each antibody in equivalent amounts. The differential binding of antibodies 9.6 and 35.1 to T cells from nonhuman primates further supports the interpretation that the differences between the antibodies in their effects on E rosette formation and natural killer function stem from the fact that they bind to distinct epitopes of Tp50. The implications of these findings for understanding the functions of Tp50 molecules are discussed.

Animals↗
PubMed1985

Surface immunoglobulin of B-lymphocytic tumours as a therapeutic target.

The surface immunoglobulin of B-lymphocytic tumours is well characterized at the molecular level and in its idiotypic determinants offers antigenic targets which are effectively tumour-specific. Anti-idiotype antibodies raised individually for each tumour have been used for passive serotherapy in animals and man. The advent of monoclonal technology has added further precision, and can readily provide the large quantities of antibody which might sometimes be necessary. However, the therapeutic use of unmodified anti-idiotype has yielded a significant remission in only a minority of cases. Some factors thwarting the antibody can be readily identified; prominent among these are extracellular idiotypic immunoglobulin and antigenic modulation. Another major factor is our ignorance of appropriate effector mechanisms to be recruited, with one candidate mechanism being the activation of immunological suppressor circuits. Without such knowledge there is a large arbitrary element in the selection of antibody isotype, doses and schedules. Some groups suspect that antibody derivatives will eventually prove more effective than the native molecules. Univalent, chimeric univalent and toxin-bearing antibodies are among those being investigated. Monoclonal and molecular genetic technologies may play an increasing role in the engineering of such derivatives. The fast-growing animal lymphomas presently available as models cannot mimic more than a tiny fraction of human lymphomas. So the arena in which antibody therapy of B lymphoma will be decided is the clinic. Here the relatively innocuous nature of antibody treatment is a tremendous boon. However, with the mechanisms involved being multiple, complex and only partially understood we are unlikely to be favoured with rapid answers.

Animals↗
PubMed2002

Construction and characterization of a single-chain antibody fragment derived from thymus of a patient with myasthenia gravis.

Pathogenic anti-acetylcholine receptor (AChR) antibodies in myasthenia gravis (MG) and the corresponding animal model, experimental autoimmune myasthenia gravis (EAMG), principally recognize the main immunogenic region (MIR) of the AChR. Bivalent anti-MIR antibodies binding to the alpha-subunits of AChR result in AChR loss by antigenic modulation and complement activation. Monovalent Fab and single-chain variable fragments (scFv) of pathogenic anti-AChR antibodies can interfere with AChR binding of the pathogenic antibodies. In the present study, scFv637 was constructed from its parental Fab637, previously isolated from a thymus-derived phage display library with specificity toward anti-MIR of human AChR (hAChR), by PCR amplification. Bacterial produced scFv637 was able to bind to hAChR in standard precipitation radioimmunoassay (RIA). ScFv637 also bound to monkey AChR in situ on monkey neuromuscular junctions as showed in immunohistochemical staining. Furthermore, scFv637 was capable of inhibiting the binding of its intact IgG637 and anti-MIR mAb35 binding to hAChR up to 32.9 and 73.0%, respectively demonstrated in a competitive ELISA, and of MG patient sera from up to 45.5% in a competitive RIA. Therefore, scFv637, easier for manipulation in improvement of affinity and stability compared with its parental Fab637, may serve as an alternative candidate for specific immunotherapy in MG.

Amino Acid Sequence↗
PubMed2005

A rare transporter associated with antigen processing polymorphism overpresented in HLAlow colon cancer reveals the functional significance of the signature domain in antigen processing.

Transporter associated with antigen processing (TAP), a member of the ATP-binding cassette transporter superfamily, is composed of two integral membrane proteins, TAP-1 and TAP-2. Each subunit has a C-terminal nucleotide-binding domain that binds and hydrolyzes ATP to energize peptide translocation across the endoplasmic reticulum membrane. A motif comprising the sequence LSGGQ (called the signature motif) and the amino acid that is immediately C-terminal to this motif are highly conserved in the nucleotide-binding domains of ATP-binding cassette transporters. To search for natural variants of TAP-1 with alterations in or near the signature motif, we sequenced the TAP-1 exon 10 amplified from 103 human colon cancer samples. We found a rare TAP-1 allele with an R>Q alteration at a residue immediately C-terminal to the signature motif (R648) that occurred 17.5 times more frequently in colon cancers with down-regulated surface class I MHC than those with normal MHC levels (P = 0.01). Functional analysis revealed that the Q648 variant had significantly reduced peptide translocation activity compared with TAP-1 (R648). In addition, we found that mutations S644R, G645R, G646S, and G646D interfered with TAP-1 activity. TAP-1 G646D, which showed the most severe defect, resided normally in the endoplasmic reticulum and associated with the peptide loading complex, but failed to transport peptide across the endoplasmic reticulum membrane. Thus, a TAP-1 polymorphism adjacent to the signature motif may be a contributing factor for MHC class I down-regulation in colon cancer. Given the widespread defects in DNA mismatch repair in colon cancer, mutations at or near the signature domain can potentially modulate antigen processing.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1986

Variables affecting the killing of cultured human neuroblastoma cells with monoclonal antibody and complement.

To determine incubation conditions that result in optimal in vitro killing of human tumor cells with monoclonal antibody and complement, variables affecting the killing of cultured human neuroblastoma cells with monoclonal antibody 6-19 and baby rabbit complement were studied. Neuroblastoma target cells were stained with the fluorescent dye Hoechst 33342, which enables rapid, sensitive detection of surviving cells in conjunction with trypan blue exclusion. Maximal cell lysis was obtained at an antibody concentration of 5-10 micrograms/ml. Greater than 5 logs of cell kill were obtained with appropriate treatment conditions. No antigenic modulation was detected. Complement activity was found to be the factor which limited the extent of cell kill. Specific cell lysis increased with increasing concentration of complement. As the reaction with antibody coated cells proceeded, complement activity was depleted. This resulted in the greatest cell kill occurring during the first 10-20 min of treatment. Generation of factor(s) inhibitory to complement activity was also found. However, the effect of inhibition on limiting the extent of cell kill was much less significant than the effect of complement depletion. When compared to a single incubation of the same total duration, the reduction in complement activity with duration of incubation resulted in greater killing by multiple brief incubations with fresh complement. The depletion of complement was found to increase at a greater cell concentration. This resulted in greater proportional survival as neuroblastoma cell concentration increased. Depletion of complement activity by aggregated monoclonal antibody was found to decrease cytotoxicity. This evaluation may provide a framework for optimization of target cell destruction using complement and other monoclonal antibodies and target cells.

Antibodies, Monoclonal↗
PubMed1987

Monoclonal antibody 1F5 (anti-CD20) serotherapy of human B cell lymphomas.

Four patients with refractory malignant B cell lymphomas were treated with continuous intravenous (IV) infusions of murine monoclonal antibody (MoAb) 1F5 (anti-CD20) over five to ten days. Dose-dependent levels of free serum 1F5 were detected in all patients. Two patients had circulating tumor cells and in both cases 90% of malignant cells were eliminated from the blood stream within four hours of initiation of serotherapy. Antigenic modulation did not occur, and sustained reduction of circulating tumor cells was observed throughout the duration of the infusions. Serial bone marrow aspirations and lymph node biopsies were examined by immunoperoxidase and immunofluorescence techniques to ascertain MoAb penetration into extravascular sites. High doses (100 to 800 mg/m2/d and high serum 1F5 levels (13 to 190 micrograms/mL) were required to coat tumor cells in these compartments in contrast to the low doses that were adequate for depletion of circulating cells. Clinical response appeared to correlate with dose of MoAb administered with progressive disease (52 mg), stable disease (104 mg), minor response (1,032 mg), and partial response (2,380 mg) observed in consecutive patients. The patient treated with the highest 1F5 dose achieved a 90% reduction in evaluable lymph node disease, but the duration of this remission was brief (six weeks). This study demonstrates that high doses of 1F5 can be administered to patients with negligible toxicity by continuous infusion and that clinical responses can be obtained in patients given greater than 1 g of unmodified antibody over a ten-day period.

Adult↗
PubMed1989

In vivo use of monoclonal antibodies against murine T cell antigens.

Experiments were performed seeking conditions for the optimum use of anti-T cell monoclonal antibodies in vivo in mice. Anti-L3T4 (CD4) and anti-Lyt2 (CD8) antibodies of different subclasses (IgG2b, IgG2a, and IgM) and species (rat or mouse) were used. The results showed that (i) intraperitoneal compared to intravenous administration of the different antibodies achieved the same serum levels whether in the presence or absence of the recipient's thymus; (ii) repeated treatment with a rat IgM anti-L3T4 or a rat IgG2b anti-Lyt2 antibody was followed by inability to detect serum levels of each antibody; (iii) in vivo treatment with these antibodies caused target cell lysis, target antigen masking without cell destruction, or target antigen modulation without cell destruction and the particular effect of a given antibody could not be predicted by its isotype or specificity; (iv) neither the C5 component of complement nor antibody-dependent cell-mediated cytotoxicity mediated the action of GK1.5 antibody in vivo; (v) dose-response curves of in vivo potency of a given antibody could not be predicted by in vitro assays; (vi) thymocytes were depleted by monoclonal antibody treatment by using 1000-fold more antibody than needed to deplete peripheral lymphocytes; (vii) the rate of return of target T cells after depletion in nonthymectomized mice depended on the dose of the antibody; and (viii) thymectomy prolonged the effect of most, but not all antibodies. In thymectomized mice, CD8+ cells remained almost undetectable for prolonged periods of time after depletion while CD4+ cells returned to approximately 30% of their original level and remained constant over time after initial complete depletion. These results provide useful data for the effective use of monoclonal anti-T cell antibodies in mice. They stress the difficulty of predicting the in vivo effects of monoclonal antibodies without actually testing them in vivo. They include new insights into mechanisms of action of monoclonal antibodies and the role of thymectomy in prolonging their effect. They describe the unrecognized ability of antibodies to deplete thymocytes.

Animals↗