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PubMed1986

Accessory cells in immune suppression. III. Evidence for two distinct accessory cell-dependent mechanisms of T lymphocyte-mediated suppression.

Suppression of antibody secretion by the 2,4,6-trinitrophenol (TNP)-binding BALB/c myeloma, MOPC 315, by idiotype- and hapten-reactive suppressor T cells is mediated by secreted factors (TsF) and requires the presence of accessory cells (AC). Idiotype-specific TsF functions only in the presence of Ia+ AC and is completely idiotype specific. Moreover, no suppression is observed when myeloma targets and AC are separated by cell-impermeable membranes, indicating that the role of AC may be to bind, focus, and/or present TsF to the myeloma cells. In contrast, TNP-specific TsF inhibits myeloma function in the presence of TNP-protein and activated macrophages that are not Ia+. This form of suppression is nonspecific at the effector stage; i.e., anti-TNP TsF inhibits a non-TNP binding cell line, TEPC 15, as long as TNP-protein and activated macrophages are present. Moreover, suppression occurs even when myeloma targets and AC are separated by cell-impermeable membranes. These results are consistent with the view that hapten-reactive TsF binds to antigen on the surface of macrophages and induces these cells to secrete nonspecific immunosuppressive molecules. Thus, different types of AC may play fundamentally different roles in TsF-mediated suppression; they may either bind and present TsF to targets (as in the case of idiotype-specific TsF) or secrete nonspecific immunosuppressants as a consequence of a TsF-antigen interaction (hapten-specific TsF). Autonomous, suppressible targets provide valuable experimental systems for analyzing the cellular interactions in T cell-mediated suppression.

Animals↗
PubMed1976

Suppression of antibody responses in allogeneic mice by products of lymphoid tissue. II. Lack of antigenic specificity and immunogenetic requirements of allogeneic suppressive factor (ASF).

Mice were irradiated, infused with thymocytes and immunized with a variety of antigens, i.e., sheep or horse red blood cells (SRBC or HRBC), diphtheria toxoid (DT) or bovine gamma-globulin (BGG). The spleen cells (T.Spleen cells) were harvested 5 days later and cellfree extracts were prepared. The extracts contained an allogeneic suppressive factor (ASF) that was capable of inhibiting IgM antibody responses of allogeneic or semi-allogeneic unirradiated mice. ASF had to be injected within 24 hr of immunization to be effective and a single injection delayed, rather than abolished, the antibody response at the cellular level. However, daily injections of ASF resulted in persistent suppression of antibody response. ASF activity was antigen nonspecific, i.e., the antigen used to stimulate ASF production did not have to be the same as the antigen used to test for ASF activity. C3H T.Spleen extracts were even immunosuppressive when prepared by exposure to C3BF1 alloantigens only; such extracts suppressed antibody responses of C3BF1 and DBA/2 mice. C3H ASF was removed from extracts after incubation with C3BF1 spleen cells but not after incubation with C3H spleen cells. C3BF1 spleen cells which had been preincubated with C3H ASF were unable to generate antibody-forming cells upon transfer to irradiated C3BF1 host mice. This suggests that the ASF molecule may be or include receptors for alloantigens. The immunogenetic requirements for ASF activity were evaluated by injecting extracts from C3H, C57BL, C3BF and BALB/c T.Spleen cells into C3H, CBA, C57BL, BALB/c, DBA/2, A or C3H.A recipient mice. All extracts tested had ASF activity. However, all allogeneic recipients were not suppressed by the extract material. The suppressive activity of ASF seemed to require two (or more) antigenic differences between donors and recipients of extract material, an H-2K or I antigen difference and a second antigen difference, possibility Ig-1. In the limited numbers of strain combinations tested, T.Spleen extracts suppressed IgM antibody response only if exposed to H-2 and Ig-1 antigens, e.g., BALB/c (H-2d, Ig-1a) ASF suppressed A (H-2a, Ig-1e) but not C3H.A (H-2a, Ig-1a) or DBA/2 (H-2d, Ig-1c). Separate ASF molecules may react with separate antigens on the cell surface, i.e., with H-2 and gammaG2a. Alternatively, one ASF molecule may react with two structurally associated antigens. If the latter is correct, it is conceivable that the beta2-microglobulin which is non-covalently linked to the major component of H-2 molecules expresses allotypic antigens coded for by Ig-1 and beta2-microglobulin is one of the antigens recognized by ASF.

Animals↗
PubMed1981

Newborn T cell suppression: early appearance, maintenance in culture, and lack of growth factor suppression.

Human newborn T lymphocytes suppress the responses of adult lymphocytes to several stimuli, including the T dependent differentiation of adult B cells to plasma cells (PC) by pokeweed mitogen (PWM) stimulation. We tested blood from premature babies to show that the suppressor activity for PWM-induced B cell differentiation appeared by 26 weeks' gestation. Cord blood from full term babies delivered by Caesarean section also suppressed PC differentiation showing that maternal labor is not a prerequisite for suppression. Eleven percent of freshly isolated newborn T cells bore the putative suppressor phenotype OKT 8 and 81% had the putative helper phenotype OKT 4, so the increased suppression and diminished help of newborn T cells was not associated with an imbalance of phenotypic helper or suppressor cells. The function of newborn T cells was further investigated by establishing the cells in continuous culture with T cell growth factors. The polyclonal lines obtained suppressed adult PWM-induced PC differentiation and were inefficient helpers so their functional characteristics appear to be maintained in culture without changes in the balance of help and suppression. PHA-stimulated newborn lymphocytes were themselves efficient producers of T cell growth factors. We conclude that newborn T cells can suppress without lectin activation and that the suppressor activity that is found is a stable intrinsic characteristic of the cell.

Animals↗
PubMed1976

Synchronous regulation of VH and CH allotypes among Ig molecules in multi-heterozygous rabbits suppressed with anti-VH allotype antibody: emergence of IgA from suppression prior to IgG and IgM.

Heterozygous rabbits of genotype a1n81f73g74/a2n82f71g75 were suppressed at birth for the VH region a1 allotype. At 8 weeks of age, quantitative analysis of serum IgG, IgM, and IgA molecules showed that the VHa1 specificity was effectively suppressed in the three classes of Ig and that the suppression was extended to the CH region n81 specificity on mu-chains as well as to the CH region f73 and g74 specificities on alphaf and alphag chains. At 26 weeks of age, analysis of serum IgG and IgM molecules showed that a1 was still suppressed to approximately the same extent in both Ig classes and the suppression was still extended to the CH region n81 specificity. However, at 26 weeks, the percentage of molecules with a1 specificity had doubled among serum and colostral IgA molecules and this increase was extended to the CH region f73 and g74 specificities. Thus, the suppressed allotypes reappeared first among IgA molecules. Our data are consistent with a regulatory mechanism which controls and synchronizes the expression of the VHa and the CH allotypes expressed on the same heavy chain. The order of the re-expression of the suppressed allotypes with respect to Ig class may allow further definition of selective regulatory mechanisms for the synthesis of Ig classes.

Animals↗
PubMed1998

[Suppressibility of thyroid autonomy in endogenous and additional exogenous TSH suppression in patients with thyroid autonomy].

AIM: The aim of this retrospective study was to examine the effect of an additional exogenous thyroid hormone suppression on the 99m Technetium Thyroid-Uptake (TcTU) in patients with thyroid autonomy and endogenous TSH suppression. METHODS: 21 patients were examined in the years 1992-1996; they had a primary endogenous suppression (end) of the TSH-b and an evaluation of the TcTU. After an additional exogenous suppression (ex) of the thyroid, the first two weeks with 75 micrograms/dl and the following 2 weeks 150 micrograms/d, or depending on the bodyweight 2 micrograms/kg levothyroxin, another evaluation of the TcTU was performed. The whole patients were called group I with a TcTUend of 1.6%-7.4%. The subgroups were selected by thresholds of the TcTUend; group Ia TcTUend > or = 1.6% and < 2.5%, group lb TcTUend > or = 2.5%, group Ic TcTUend > or = 3%. RESULTS: The intraindividual comparison showed a significant decrease of the autonomous "volume" after exogenous suppression with levothyroxin. This is shown by the following values of the TcTU: group I TcTUend = 3.47 +/- 1.65 and TcTUex = 2.91 +/- 1.38, which means a reduction of 20 rel.% (p < or = 0.001); group Ia TcTUend = 2.05 +/- 0.27, TcTUex = 1.85% +/- 0.22, which means 10 rel.% (p < or = 0.001); group Ib TcTUend = 4.18 +/- 1.59, TcTUex = 3.45% +/- 1.34, which means 20 rel.% (p < or = 0.001); group Ic TcTUend = 5.00% +/- 1.43, TcTUex = 4.05% +/- 1.32, which means 20 rel.% (p < or = 0.001). CONCLUSION: Supposing a structural variability of autonomous thyroid tissue with heterogenous TSH receptors our study shows a significant additional exogenous suppression in already endogenous suppressed TSH receptors.

Adult↗
PubMed2002

Tumor-specific activation of hTERT-derived promoters by tumor suppressive E1A-mutants involves recruitment of p300/CBP/HAT and suppression of HDAC-1 and defines a combined tumor targeting and suppression system.

Adenovirus (Ad) E1A proteins are transcriptional regulators with antioncogenic but also transforming properties. We have previously shown that transformation-defective Ad5 E1A-derivatives are excellent tumor suppressors. For tumor-specific expression of the E1A-derivatives we intend to use tumor specific human telomerase reverse transcriptase (hTERT) core promoters. Here, we show that Spm2 and other E1A proteins with an intact amino terminus activated all hTERT constructs 10-20-fold in malignant tumor cells but not in primary fibroblasts, without affecting the activity of endogenous telomerase. The transcription rate in tumor cells was in the range of transcription from the SV40 promoter, which qualifies an E1A-hTERT system as a putative tumor targeting/expression system. The activation of the hTERT promoter by E1A was enhanced upon deletion of the Wilms' tumor 1 negative regulatory element and maintained high after deletion of the adjacent c-Myc-responsive E-box, demonstrating an important role of the remaining sequences that contain several Sp1-motifs. E1A-mediated hTERT activation was independent from the presence of the conserved region 3 (CR3) of E1A but dependent on E1A's binding to p300/CBP and recruitment of its histone acetyltransferase activity. Moreover, E1A-Spm2 and histone deacetylase-1 behaved as antagonists with respect to the regulation of transcription from the hTERT promoter. Overall, hTERT promoter/E1A-Spm2 systems may turn out to be excellent tools for transcriptionally targeted anticancer gene therapy.

Adenovirus E1A Proteins↗
PubMed1997

The effect of a suppressed rad52 mutation on the suppression of rad6 by srs2.

We have cloned a suppressor of a temperature-sensitive rad52 allele and found it to be a mutation in PUP1, a gene encoding a protease subunit of the 20s proteasome. This identity prompted us to examine the interrelationship among PUP1, RAD52, SRS2 and RAD6 because srs2 mutations not only suppress some rad52 mutations but also suppress deletions of rad6, a gene encoding a protein in the ubiquination-dependent proteolysis pathway. We have found that while srs2 suppresses the UV sensitivity of rad6 in the presence of RAD52, srs2 cannot suppress rad6 when the temperature-sensitive allele of rad52 is present. This inability of srs2 to suppress rad6 is irrespective of the incubation temperature or whether pup1 is suppressing the temperature-sensitive rad52 mutation.

Alleles↗
PubMed1984

Central suppression of monoclonal B cells: DNP-MGG suppresses proliferation and immunoglobulin synthesis in anti-DNP-secreting hybridoma and myeloma.

Our laboratory has established that 2,4-dinitrophenyl-conjugated mouse IgG (DNP-MGG) can specifically suppress the anti-DNP secretion in hybridoma 35-12 and plasmacytoma MOPC-315 cells. To further study the mechanism of this suppression, the effect of DNP-MGG on anti-DNP synthesis and cell proliferation was investigated in these cell lines. Cultured tumor cells (1 X 10(6] were injected ip into syngeneic mice. These mice were then given either 1 mg MGG or 1 mg DNP-MGG. At different days after injection, tumor cells obtained from these mice were assayed for anti-DNP secretion, anti-DNP synthesis, cell proliferation, and tumor cell size. When the anti-DNP secretion was suppressed by DNP-MGG, the intracellular synthesis of anti-DNP, demonstrated by [3H]leucine incorporation into DNP-binding activity, was also suppressed. Simultaneous assays of [3H]thymidine incorporation demonstrated that proliferation was also suppressed. Tumor cells injected ip into mice normally become small nonsecreting cells and later return to preinjection size and secrete antibody. Those cells whose antibody synthesis and proliferation were suppressed by DNP-MGG remained smaller.

Animals↗
PubMed1984

Allotype suppression in the chicken. V. Abnormal isotype ratios of chronically suppressed IgM and IgG allotypes.

Chronic allotype suppression was generated in M-1 (C mu), G-1 (C gamma) heterozygous B14 line chickens either by embryonal injection or by maternal transfer of anti-M-1b allotype antibodies. Using a sensitive radioimmunoassay to detect the suppressed IgM-1b, a striking disparity was observed between the degree of suppression of the IgM-1b allotype and that of the genetically linked IgG-1i allotype. The amount of suppressed IgM-1b ranged between 0.2 and 3% of total serum IgM in chronically suppressed birds. The levels of the genetically linked IgG-1i, however, comprised 5 to 25% of total serum IgG in such birds. The allotypes measured in suppressed chickens were qualitatively identical to those in normal, nonsuppressed birds by serological criteria. These results are discussed within the context of isotype regulation in the chicken.

Alleles↗
PubMed1984

An unusual suppression of immune response: pretreatment with Poly(Glu60,Phe40) suppresses response to poly(Glu60,Phe40).

The synthetic random copolymer poly( Glu60 , Phe40 ) ( GPhe ) is an excellent immunogen in SWR/J (H-2q) mice. The intravenous injection of soluble GPhe by itself led to antibody production and GPhe -specific T-lymphocyte proliferation. The proliferating lymphocyte was sensitive to anti-Thy 1.2 and anti-Ly 1 antisera. A subsequent immunization with GPhe should therefore lead to an enhanced response. Yet, a single intravenous injection of an aqueous solution of GPhe suppressed the immune response to a subsequent immunization with GPhe in CFA as measured by GPhe -specific plaque-forming colonies, ELISA, T-cell proliferation, and delayed-type hyper-sensitivity. The suppression was not transferable from pretreated mice into normal or irradiated syngeneic recipients with either sera or lymphoid cells. The antibody generated from the pretreatment could not be responsible for the suppression as injection of SWR anti- GPhe antibody into SWR/J mice enhanced, rather than suppressed, the response to the subsequent immunization with GPhe . Pretreatment of mice with a rabbit anti-idiotypic antiserum produced against (SWR anti- GPhe antisera) had no effect on the immune response to GPhe . Thus, the suppression cannot be explained by a simple B-cell tolerance mechanism. This type of unusual suppression was observed only with mice of H-2q haplotype and not with mice of H-2 haplotypes a and k which are also responders to GPhe .

Animals↗
PubMed1992

Effects of chlordiazepoxide and beta-carboline 3-carboxylic acid ethyl ester on non-suppressed and minimally-suppressed responding in the squirrel monkey.

Lever-pressing of squirrel monkeys was maintained under a multiple fixed-interval (FI) 5-min schedule of food presentation. In one component, responding was suppressed to various degrees by the presentation of electric shock following each 30th response. When responding was either substantially or minimally suppressed, intermediate doses of chlordiazepoxide (CDAP, 1-30 mg/kg) increased both suppressed and non-suppressed responding. Beta-carboline 3-carboxylic acid ethyl ester (beta-CCE, 0.1-3 mg/kg) had little effect at low to intermediate doses (0.1-0.3 mg/kg) and decreased both minimally-suppressed and non-suppressed responding to a comparable extent at higher doses. Repeated daily dosing with beta-CCE (up to 10 mg/kg) resulted in rapid tolerance to its rate-decreasing effects. As agonists do not typically exhibit rapid tolerance for anxiolytic efficacy, the current results suggest that some behavioral effects of inverse agonists may not be strictly opposite those of benzodiazepines.

Animals↗
PubMed1990

Estrogen induced suppression of collagen arthritis. V: Physiological level of estrogen in DBA/1 mice is therapeutic on established arthritis, suppresses anti-type II collagen T-cell dependent immunity and stimulates polyclonal B-cell activity.

Immunization of castrated female DBA/1 mice with rat type II collagen (CII) induces severe polyarthritis with an onset 3-5 weeks after immunization and with 80-100% incidence. Estrogen treatment, inducing physiological 17 beta-estradiol (E2) levels, during a limited period before and after the immunization, or during another period before the expected onset of arthritis, delayed the arthritic onset by approximately 10 days but did not affect the incidence of severity of arthritis. Treatment with physiological doses of E2 after onset of arthritis decreased severity and duration of disease. The T-cell dependent anti-CII autoantibody response was suppressed if the E2 treatment was given immediately before and after CII immunization and was not significantly affected if E2 treatment was given after CII immunization. Neither the total anti-CII Ig levels nor the anti-CII IgG2a levels correlated with development of arthritis. We also titrated the serum levels of estrogen and recorded the vaginal smear response after injections of various doses of E2. This enabled us to work in a physiological range of estrogen levels, spanning the levels found at the end of pregnancy and those found during the normal estrous cycle. These levels were found to suppress antigen-specific T-cell functions but enhance certain B-cell activities since the delayed type hypersensitivity (DTH) reaction against CII was suppressed while the total number of splenic Ig-secreting cells increased. These findings suggest that estrogen in physiological doses is therapeutic for the development of collagen-induced arthritis and that estrogen exerts dualistic effects on the immune system by suppressing T-cell functions and stimulating certain B-cell activities. The suppressive effect on arthritis could not be explained by suppression of anti-CII autoantibody response and must therefore depend on other T-cell-mediated functions.

Analysis of Variance↗
PubMed1999

Suppression of agglomeration in fluidized bed coating. III. Hofmeister series in suppression of particle agglomeration.

PURPOSE: Fourteen kinds of salts consisting of various cations and anions in the Hofmeister series were used as additives for suppression of particle agglomeration in the fluidized bed coating. We attempted to clarify the relationship between the suppression effect of the salts and the Hofmeister series of their consistent ions. METHODS: Fluidized bed coating was carried out with hydroxypropylmethyl cellulose (HPMC) aqueous coating solution containing the salts and Celphere as core particles. To elucidate the salting-out power of the salts for HPMC, the transmittance of the coating solutions at 600 nm was measured at various temperatures and the phase separation temperature (T(PS)) was determined from the values at 50% transmittance. RESULTS: A high suppression effect was observed when the salts including high order ions in the Hofmeister series were added to the coating solution. T(PS) decreased in the presence of the salts except for sodium iodide and sodium thiocyanate and lowered with the higher order ion in the Hofmeister series. The particle agglomeration was suppressed with decrease in T(PS) of the HPMC aqueous coating solution. CONCLUSIONS: It has been suggested that the suppression effect of a salt on the particle agglomeration depended on the salting-out power of the salt. We regard sodium citrate and potassium citrate as very useful pharmaceutical additives for the suppression of particle agglomeration in actual pharmaceutical coating.

Algorithms↗
PubMed1984

Suppression of natural killer cell activity by adherent effusion cells of cancer patients. Suppression of motility, binding capacity and lethal hit of NK cells.

Adherent cells from carcinomatous pleural effusions of lung cancer patients were tested for their ability to suppress natural killer (NK) cell activity, and the mechanism involved in the suppression of NK cell activity was determined. Adherent effusion cells (AEC) were isolated from malignant pleural effusions of patients by centrifugation discontinuous Ficoll-Hypaque gradients and adherence to serum-coated plastic dishes, and large granular lymphocytes (LGL) were purified from the peripheral blood of normal individuals by centrifugation on discontinuous Percoll gradients and further depletion of high-affinity sheep erythrocyte rosette formation. LGL-mediated lysis of K562 cells was suppressed when LGL were cultured with AEC for 20 h, then washed and tested in a 4-h 51Cr release assay. More profound suppression of NK cell activity was observed when cytotoxicity was assayed in flat-bottomed wells rather than in round-bottomed wells. Cytotoxicity assays conducted at the single cell level in agarose revealed that the frequency of LGL binding to K562 cells and of dead conjugated target cells was reduced after overnight contact with AEC. In agarose microdroplet assays, functional LGL from normal donors exhibited definitive motility, expressing polarized shape. In contrast, a small number of LGL with non-polarized configuration migrated from the agarose droplet after overnight culture with AEC. These results indicate that functionally suppressed NK cells lose their motility, binding capacity and killing activity, which could be responsible for the suppression of NK cell activity by AEC.

Cell Adhesion↗
PubMed1997

Dexamethasone suppresses release of soluble TNF receptors by human monocytes concurrently with TNF-alpha suppression.

Glucocorticoids suppress many monocyte functions, including endotoxin-stimulated release of TNF-alpha. Monocytes also release soluble receptors for TNF (sTNF-R), which can modulate TNF bioactivity. We therefore examined the effects of the glucocorticoid, dexamethasone, on the release of soluble forms of the 55 kDa and 75 kDa receptors for TNF (sTNF-R55 and sTNF-R75) by human monocytes and the human monocytic Mono Mac 6 cell line. Peripheral blood mononuclear cells (PBMC) spontaneously released 406 +/- 181 pg/10(6) cells of sTNF-R75 over 18 h in culture and Mono Mac 6 cells released 554 +/- 29 pg/10(6) cells. Lipopolysaccharide (LPS) exposure increased release of sTNF-R75 by 54 and 217%, respectively. Dexamethasone suppressed both spontaneous and LPS-stimulated release. The effect of dexamethasone was concentration dependent. At 1 mumol/L, dexamethasone suppressed the LPS-stimulated release of sTNF-R75 by 86% in PBMC and by 40% in Mono Mac 6 cells. Neither PBMC nor Mono Mac 6 cells released measurable amounts of sTNF-R55, but spontaneous release of sTNF-R55 from purified human monocytes (55 +/- 2 pg/10(6) cells over 18 h) was reduced by 45% in the presence of dexamethasone. Dexamethasone reduced bioactive TNF in PBMC cultures, as well as immunoassayable TNF-alpha, which indicates that suppression of TNF-alpha release was biologically more important than suppressed release of soluble inhibitors. Similar concurrent suppression of IL-1 beta and IL-1ra release occurred in PBMC and Mono Mac 6 cultures exposed to dexamethasone.

Adult↗
PubMed2000

Glucocorticoids suppress tumor necrosis factor-alpha expression by human monocytic THP-1 cells by suppressing transactivation through adjacent NF-kappa B and c-Jun-activating transcription factor-2 binding sites in the promoter.

Glucocorticoid drugs suppress tumor necrosis factor-alpha (TNF-alpha) synthesis by activated monocyte/macrophages, contributing to an anti-inflammatory action in vivo. In lipopolysaccharide (LPS)-activated human monocytic THP-1 cells, glucocorticoids acted primarily on the TNF-alpha promoter to suppress a burst of transcriptional activity that occurred between 90 min and 3 h after LPS exposure. LPS increased nuclear c-Jun/ATF-2, NF-kappaB(1)/Rel-A, and Rel-A/C-Rel transcription factor complexes, which bound specifically to oligonucleotide sequences from the -106 to -88 base pair (bp) region of the promoter. The glucocorticoid, dexamethasone, suppressed nuclear binding activity of these complexes prior to and during the critical phase of TNF-alpha transcription. Site-directed mutagenesis in TNF-alpha promoter-luciferase reporter constructs showed that the adjacent c-Jun/ATF-2 (-106 to -99 bp) and NF-kappaB (-97 to -88 bp) binding sites each contributed to the LPS-stimulated expression. Mutating both sites largely prevented dexamethasone from suppressing TNF-alpha promoter-luciferase reporters. LPS exposure also increased nuclear Egr-1 and PU.1 abundance. The Egr-1/Sp1 (-172 to -161 bp) binding sites and the PU.1-binding Ets site (-116 to -110 bp) each contributed to the LPS-stimulated expression but not to glucocorticoid response. Dexamethasone suppressed the abundance of the c-Fos/c-Jun complex in THP-1 cell nuclei, but there was no direct evidence for c-Fos/c-Jun transactivation through sites in the -172 to -52 bp region. Small contributions to glucocorticoid response were attributable to promoter sequences outside the -172 to -88 bp region and to sequences in the TNF-alpha 3'-untranslated region. We conclude that glucocorticoids suppress LPS-stimulated secretion of TNF-alpha from human monocytic cells largely through antagonizing transactivation by c-Jun/ATF-2 and NF-kappaB complexes at binding sites in the -106 to -88 bp region of the TNF-alpha promoter.

Activating Transcription Factor 2↗
PubMed1974

Alloantiserum-mediated suppression of histocompatibility-linked Ir-gene-controlled immune responses. Suppressive effects of IgG fragments derived from alloantisera.

Fab, Fc, and F(ab)'(2) fragments were prepared by enzymatic hydrolysis of the IgG fraction of strain 13 antistrain 2 alloantisera. These fragments were not cytotoxic to lymphocytes bearing strain 2 histocompatibility antigens, but the Fab and F(ab)'(2) fragments retained functional combining sites as indicated by their ability to suppress the cytotoxicity mediated by the intact antistrain 2 antibodies. The F(ab)'(2) fragments were much more efficient as inhibitors in this system than the Fab fragments. F(ab)'(2) at 0.06 mg/ml and 0.45 mg/ml Fab produced comparable degrees of suppression. The F(ab)'(2) at 0.06 mg/ml completely suppressed DNP copolymer of L-glutamic acid and L-lysine (GL)-stimulated tritiated thymidine incorporation. The monovalent Fab at 0.45 mg/ml, however, had no significant effect on the in vitro responses to DNP-GL. Addition of the intact alloantisera can be delayed 3 h after initiation of the antigen-stimulated cultures with no loss of suppression. After a delay of 6 h 45% suppression was observed. The requirement for the divalent molecule and the observation that effective suppression of the in vitro responses is still obtained when the alloantiserum is added several hours after initiation of the cultures both suggest that the immunosuppression results from an active process affecting the lymphocyte membrane that renders the cell refractory to the antigenic stimulus.

Alanine↗