EBM Email Content Delivery
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Cone, R. E.
Right arrow Articles by Little, C. H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Cone, R. E.
Right arrow Articles by Little, C. H.
Experimental Biology and Medicine 227:438-444 (2002)
© 2002 Society for Experimental Biology and Medicine

MINIREVIEW

Soluble T-Lymphocyte Antigen-Specific Immunoproteins: A Progress Report1

Robert E. Cone2,*, George M. Georgiou{dagger} and Colin H. Little{ddagger}

* Department of Pathology, University of Connecticut Health Center, Farmington, Connecticut 06030-3105;
{dagger} National Aging Research Institute, Parkville 3050, Australia; and
{ddagger} Mount Waverley, Victoria 3149, Australia.


   Abstract
Top
 Abstract
Introduction
 Properties of Soluble Antigen...
 References
 
T-cell-derived proteins that bind nominal (non-MHC-associated) antigen specifically (TABM) express V and C region epitopes of the T-cell receptor (TCR) for antigen and have a significant similarity in amino acid sequence to TCR {alpha}-chain V and C region. The presence of these immunoproteins in human serum and a specific increase in serum TABM in infectious disease, chemical sensitivity, and food intolerance suggest that TABM may impact on pathogenesis through the modulation of cell-mediated immunity, the antigen-specific concentration and delivery of immunoregulatory cytokines such as TGF-ß and elastase, and the induction of the release of substance P by sensory neurons. In this Minireview update, we describe advances in the detection and quantitation of human TABM by monoclonal antibodies, and the association of increased human serum TABM titers in infectious disease, chemical sensitivity, and food intolerance. We suggest that the immunomodulatory mode of action of these immunoproteins may be the antigen-specific focusing of cytokines associated with TABM.

Key Words: serum TABM • TGFß • immunoregulation • infectious and immune-mediated disease


   Introduction
Top
 Abstract
 Introduction
Properties of Soluble Antigen...
 References
 
TThe specificity of the immune response is determined at the cellular level by membrane-associated antigen receptors that participate in the clonal activation of T and B cells. These specifically activated cells then effect humoral or cell-mediated activity towards the antigen. Circulating immunoglobulins can be considered the soluble expression of the B lymphocyte membrane immunoglobulin receptor for antigen because the combining site of the circulating immunoglobulin is identical to the combining site of the membrane immunoglobulin on the B cell that was the precursor of the antibody-producing plasma cell. However, the constant region that determines the effector function of secreted immunoglobulin may differ from that of the membrane immunoglobulin of the precursor of the plasma cell secreting the immunoglobulin. Moreover, the effector function of secreted immunoglobulins may be expanded by the binding of molecules (e.g., complement) produced by other cells. In contrast to B lymphocytes, much of the specific activity of T lymphocytes is cell-mediated by membrane-associated receptors (TCR) that bind antigen presented by antigen-presenting cells and associated with major histocompatibility complex (MHC) class I and class II glycoproteins. Similar to the "B cell strategy," nonantigen-specific cytokines secreted by T lymphocytes activated by antigen extend and amplify the activity of T cells to other cells. The relatively short half-life of these cytokines requires that the functional activity of these biological response modifiers is focused to an antigenic site. Thus, if cytokines were "targeted" to a specific antigenic site distant from the point of origin of the cytokine (similar to complement bound by an immunoglobulin that is binding antigen), T cell-mediated immunoregulation could be extended and effected specifically.

Although the membrane-associated TCR is specific for processed antigen presented by MHC glycoproteins, some T cells produce extracellular (soluble) "immunoproteins" that bind specifically to non-processed antigen (TABM) and mediate immunoregulation and/or hypersensitivity (reviewed in Refs.1 and 2). TABM and functionally defined "antigen-specific suppressor factors" share many characteristics, and TABM have themselves been shown to have immunoregulatory activity (1–6). Although TABM still need to be defined at the genomic level and further defined at the proteomic level, this updated Minireview will consider a possible mode of action and the expression of TABM in various pathologic conditions.


   Properties of Soluble Antigen-Specific T-Cell Immunoproteins
Top
 Abstract
 Introduction
 Properties of Soluble Antigen...
References
 
Relation to the TCR.
Soluble antigen-specific T-cell immunoproteins can be categorized according to their biological and/or antigen binding function (Table IGo). Proteins that induce regulatory T cells were termed "T suppressor-inducer factor" (TsFi, when the use of "suppressor" was academically correct), and proteins that effect the regulation of other T cells were termed "T suppressor effector factor" (TsFe). Both TsFs are Mr 50,000–110,000 and composed of an antigen-binding polypeptide chain and a biologically active, nonantigen-binding chain (1, 2, 4). TsFi and TsFe are antigenically distinct (1, 2, 4) although both share an epitope recognized by monoclonal antibodies to TCR{alpha}-chains (4, 5, 7, 8). TsFe may also possess epitopes recognized by anti-TCRß (9). This could be due to an additional polypeptide chain; however, the expression of TsFi and TsFe depends on structural genes for TCR{alpha}, and ß, respectively (7, 9), suggesting that these polypeptide chains may be derived from TCR gene products. Moreover, in vitro translation of mRNA for a TCR{alpha}-chain produced an Mr-30,000 polypeptide chain that binds non-processed antigen and has immunoregulatory activity (10). The amino termini of murine (T cell hybrid derived) TABM specific for azobenzenearsonate (ABA) or nitrophenyl (NP) have a similar but not identical amino-terminal sequence, and the amino acid sequence of a trytic digest of an NP-specific murine TABM shows significant similarity (but non-identity) to the C-region of murine TCR{alpha}-chains (4, 11). Human TABM also bear a TCR C{alpha} epitope (12). Whether TABM are the products of separate, TCR-related structural genes or are a postsynthetic modification of a TCR{alpha}-chain that could result in a soluble molecule (13) remains to be determined.


View this table:
[in this window]
[in a new window]
  		Table I. Soluble Antigen-Specific T Cell Proteins
 
Polypeptide Chain Structure.
Murine TABM are >45% hydrophobic amino acids and, therefore, these hydrophobic molecules are difficult to study (11). Although TABM bear TCR C{alpha} and sometimes Cß epitopes and their expression depends on TCR structural genes, (limited) amino acid sequence suggests that TABM are not TCR chains (11). Many sizes ranging from Mr 22,000 to 33,000 protomers to Mr 110,000 or to aggregates >106 have been reported (1–4). The polydisperse nature of TABM may be due to their hydrophobic properties that facilitate aggregation. TABM found in serum (6, 12, 14) are precipitated by 43%–50% ammonium sulfate, have the electrophoretic mobility of {alpha} globulins (14), and have a molecular size >106 (12) as evidenced by molecular sieving of non-denatured molecules. These properties of TABM indicate that TABM may "contaminate" preparations of other serum proteins. Reduction and denaturation of these large multimers produces Mr-33,000 molecular species. In addition, TABM may often be non-covalently associated with cytokines (vide infra) and, therefore, may be perceived as large structures composed of different polypeptide chains.

Serum TABM Response to Immunization.
Immunization of mice with protein antigens (15) or trinitrophenylated cells (5, 16) induces an increase in serum of TABM specific for the immunogen when the immunogen is injected with an adjuvant. In these studies, antigen-specific TABM were detected in immune serum by a sandwich ELISA that used antigen-coated microtiter trays and polyclonal or monoclonal anti-TABM to detect serum TABM binding to antigen (2, 5, 15–17). Titers of serum TABM rise when immunization favors cell-mediated immunity, although the rise is more pronounced during a humoral immune response (2, 5, 15, 16). SCID mice do not produce TABM after immunization. However, TABM but not immunoglobulins are produced by SCID mice reconstituted with thymocytes (15), suggesting that serum TABM are produced by T cells but not B cells. In addition, TABM specific for the immunogen may be detected when immunoglobulins specific for the immunogen are not produced (12, 16). In fact, some TABM specific for the same epitope as immunoglobulins are detected more readily when immunoglobulins are removed from the immune serum before the antigen-capture ELISA (Malley A, personal communication). These observations suggest that immunoglobulins may compete with TABM for the same epitope because the serum concentration of TABM is <50 µg/ml (14).

Although TABM express a TCR{alpha} epitope, unlike the TCR, TABM bind specifically to nominal antigen. However, TCR{alpha}+,ß- TABM bind nominal antigen, but TCR{alpha}+ß TABM do not bind nominal antigen (6, 12, 16). Perhaps an associated polypeptide chain prevents the binding of nominal antigen. Moreover, TABM are highly aggregated (>10 protomeric units), and these multimers may be able to ligate nominal antigen. In this regard, the avidity of TABM for antigen is 10- to 100-fold less than that of immunoglobulins, further complicating the detection of TABM in an immune serum. Despite this, ELISA of immune serum for TABM demonstrated that the rise in antigen-specific TABM during immunization peaks 24–48 hr earlier than the peak of immunoglobulins, and TABM titers decrease, whereas immunoglobulin titers are maintained (15). This decrease in serum TABM specific for the immunogen could be due to a cessation of TABM production and/or competition between TABM and immunoglobulins for the same epitope. A secondary challenge induces a more rapid increase in TABM for the immunogen and a higher TABM titer, indicating that TABM production exhibits immunologic memory (15). Because TABM are a T cell product, the serum TABM response reflects a humoral T cell response. Human TABM are produced by CD4 or CD8 T cells (3) but not B cells (12). As discussed below, the cellular origin of the TABM may influence their function.

Serum TABM Regulate Delayed-Type Hypersensitivity (DTH).
The injection of antigen into the anterior chamber (AC) of an eye of a mouse or a rat and immunization of the animal to the same antigen inhibits cell-mediated immunity and IgG2 antibody production to the antigen. The production of IgM and IgG1 antibody to the antigen is not affected or may even be enhanced. This anterior chamber-associated immune deviation (ACAID) has been a powerful tool in dissecting the activation of regulatory T lymphocytes and eye-immune system interactions (reviewed in Ref. 18). TCR C{alpha}+ TsFi has been demonstrated in the sera of mice receiving an AC injection of herpes virus (8). AC injection of naive mice with trinitrophenylated (TNP) spleen cells (17), proteins, or trinitrophenylated proteins (5, 19) potentiated or induced the appearance of TABM specific for the AC-injected antigen. That these serum TABM mediate the suppression of DTH imposed by intracameral injection of antigen is demonstrated by several results: Injection of the mice with cyclophosphamide prevented ACAID and the production of TABM (20); ACAID (21) or serum TABM (Wang Y, Cone RE, unpublished observations) cannot be induced in mice thymectomized as adults; and, TCR C{alpha}+ antigen-specific serum TABM produced by mice with ACAID suppress the induction of DTH when injected into immunized mice (5).

TABM Are Associated with Cytokines.
The mechanism(s) by which TABM suppress DTH has not been elucidated. However, TNP-specific TsFe that effects the suppression of DTH was shown to be associated with prostaglandin (22). Moreover, TsF prepared by incubation of TABM-producing cells in vitro with indomethacin was not suppressive providing more evidence, suggesting that prostaglandin associated with TsF suppressed DTH. NP-specific TABM produced in vitro by a T cell hybrid are non-covalently associated with IL-10 produced by the T cell hybrid (4). In addition, mice with ACAID to TNP produce TNP-specific serum TABM associated with IL-10 (Wang Y, Cone RE, unpublished observations). These IL-10-associated TABM will suppress DTH to TNP when injected i.v. into TNP-sensitized mice. Although TABM are not produced by adult-thymectomized mice, injection of TNP-specific, ACAID-inducing TABM do not induce ACAID when injected into adult-thymectomized-mice (Wang Y, Cone RE, unpublished observations). These findings suggest that the induction of ACAID by TABM may require the presence of thymic regulatory T cells activated by TABM and antigen.

Human TABM non-covalently associated with TGFß1 or TGFß2 are found in non-immune (12) sera and antigen-specific TABM from the sera of individuals sensitized to toluene (benzoic acid specific ) (6, 23), milk proteins (casein, {alpha}-lactalbumin, and ß-lactoglobulin) (24), or Candida (mannan) (6). As shown in Figure 1Go (A and B), the amount of TABM-associated TGF-ß detected by ELISA increases or decreases specifically when the TABM are incubated with homologous antigen (6, 23). The dose-response relationship showing the increase in TGFß at optimal concentrations of specific antigens suggests that the interaction of the TABM with antigen "activates" the associated TGFß. The activated TGFß would suppress the production of IFN-{gamma} by T lymphocytes (6). TCRC{alpha}+ non-specific suppressor factor detected in human ascitic fluid is associated with TGFß (25). Perhaps the non-specific suppressor factor may be TABM associated with TGFß.



View larger version (30K):
[in this window]
[in a new window]
  		Figure 1. Specific interaction of TABM with antigen increases (antigenically) active associated TGF-ß. Five hundred nanograms of serum TABM isolated by monoclonal antibody (3C9) and affinity for Candida mannan (A) or benzoic acid (B) were incubated with the designated antigens for 30 min and were then assayed for TGF-ß2 by ELISA.

 
TABM may function by antigen-specific "targeting" of cytokines. Although to date only prostaglandin, IL-10, or TGFß have been detected associated with TABM, other cytokines produced by a TABM-producing cells may also be associated with TABM. It is probable that TABM are associated with more than one cytokine. In addition, elastase has been found to be functionally and physically associated with a murine antigen-specific suppressor factor produced by a T cell hybrid (26). Our laboratory has detected elastase associated with a benzoic acid-specific TABM (Fig. 2Go) isolated by monoclonal anti-TABM and affinity for benzoic acid. Perhaps proteolytic activity associated with this TABM (Fig. 3Go) is responsible for proteolytic "activation" of TGF-ß after the TABM binds antigen. Moreover, the focusing of cytokines by TABM, particularly TGFß, could lead to untoward collateral effects in addition to immunoregulation. TGFß associated with TABM will induce the secretion of substance P and will amplify the effect of substance P on sensory neurons (23). As discussed below, TABM could increase pain, muscle contractions, and mast cell-mediated effects via the action of TABM-derived TGFß on the release and activity of substance P.



View larger version (30K):
[in this window]
[in a new window]
  		Figure 2. Proteolytic activity and elastase associated with TABM. Benzoic acid-specific TABM isolated by monoclonal 3C9 and affinity for benzoic acid from the sera of toluene-sensitive patients were coated to microtiter trays and assayed by ELISA with monoclonal anti-TABM 3C9 (A) or monoclonal anti-human elastase (B).

 


View larger version (60K):
[in this window]
[in a new window]
  		Figure 3. Proteolytic activity associated with TABM. Benzoic acid-specific TABM (Fig. 2Go) or TABM specific for Candida mannan (CTAB, Fig. 1AGo) were assayed for proteolytic activity using the Pierce Protease Assay. The increase in the optical density of dinitrophenol (cleaved from DNP-albumin) is an indicator of the proteolysis of DNP-BSA.

 
Monoclonal Anti-(Human) TABM.
The characterization and definition of TABM has been complicated by the hydrophobic nature of these polypeptides, the use of only polyclonal antibodies to human TABM, and the lack of cloning of TABM structural genes. These problems have been approached by the generation and use of monoclonal antibodies to human TABM (12). Human serum Cohn Fraction III proteins rich in TABM were fractionated further by ammonium salt precipitation, cationic exchange chromatography, and immunoadsorption of the fractionated proteins. The resulting proteins were >Mr 106 polypeptides that, when reduced and denatured, were resolved by SDS-PAGE as Mr 33,000 proteins. These proteins reacted with polyclonal anti-TABM antibodies in ELISA and monoclonal antibodies to human TCR C{alpha}-chains, but were not recognized by antibodies to human immunoglobulin µ,{gamma},{alpha}-chains, immunoglobulin {kappa},{lambda}-chains, or human serum albumin. However, TGFß (12) and elastase (Fig. 2Go) were detected in the TABM preparation. Monoclonal antibody prepared against these proteins recognized TABM+ preparations, Mr 33,000 serum proteins, and proteins produced by HUT78 (T cell) lymphoma in culture, but did not bind to human serum albumin, TGFß, B lymphoma proteins immunoglobulins (12), or elastase (Cone RE, unpublished observations). Monoclonal anti-TABM does not detect lymphocyte surface proteins, but does detect intracellular proteins on some mononuclear cells (12). The identity of these cells has not been made, but TABM+ cells have been detected in the T cell zone of germinal centers (12).

Detection of TABM to Infectious Agents, Food Antigens, or Chemicals in Infectious Disease, Gastrointestinal Disturbance, or Chemical Sensitivity.
Serum TABM specific for various antigens have been detected in human sera by ELISA with polyclonal (14, 23) or monoclonal (6, 12, 23) anti-TABM. As shown in Figure 4Go, sera from individuals with suspected inflammatory bowel disease have elevated TABM titers to several food antigens. Elevated serum TABM titers to casein or {alpha}-lactalbumin have been found in individuals intolerant to milk (12, 24) (Table IIGo). Women susceptible to recurrent vulvovaginal candidiasis have elevated serum TABM titers to Candida mannan (6), which may indicate a basis for reduced cell-mediated immunity to Candida in such individuals. Similarly, individuals with chronic or asymptomatic filariasis have elevated serum TABM titers to filarial antigens (12), which may reflect reduced cell-mediated immunity to filaria. Patients sensitized to toluene (by industrial exposure) and symptomatic to an exposure to toluene or benzene have elevated serum TABM titers specific for benzoic acid (a breakdown product of toluene) (23). Antigenically (biologically) active TGFß associated with benzoic acid-specific or Candida mannan-specific TABM specifically increased when these TABM were incubated with antigen in optimal proportion (6, 23) (Fig. 1Go). For benzoic acid-specific TABM, this effect was observed for both conjugated and unconjugated benzoic acid. The activated TGFß may induce neurological effects directly or through substance P (23). Accordingly, we suggest that the antigen-specific concentration of cytokines, particularly TGFß, may produce untoward effects (Fig. 5Go). In addition, the apparently non-specific elevation of serum TABM in HIV+ symptomatic individuals (3) may be responsible for an early downregulation of cell-mediated immunity to the virus. Thus, the detection of antigen-specific TABM indicates that these immunoproteins represent a relatively uncommon immune response that, in fact, may be necessary to achieve a protective balance against more damaging cell-mediated immunity. However, like any other "double-edged sword" of the immune system, TABM themselves may participate in some pathologic conditions. An increase in a TABM titer specific for melanoma antigen MAGE III peptide have been detected in the sera of some individuals with melanoma (3) and in individuals vaccinated with MAGE III-peptide-pulsed antigen-presenting cells that did not produce T cells cytotoxic for melanoma cells (3). Thus, in addition to mediating certain pathologic conditions, TABM may provide an indicator of the efficiency of vaccination to induce humoral and/or cell-mediated immunity.



View larger version (28K):
[in this window]
[in a new window]
  		Figure 4. Antigen binding by serum TABM in gastrointestinal disorder. Serial dilutions of sera from two patients (A and B) with gastrointestinal disorder or serum from a non-affected individual (NHS) were added to microtiter trays coated with the designated antigens. Bound TABM were detected by the addition of monoclonal anti-TABM 3C9 and alkaline phosphatase-conjugated anti-murine IgG. The titer is the reciprocal of the highest dilution of the serum giving an optical density 2-fold higher than that obtained without the addition of the serum. a-Lactal, {alpha}-lactalbumin; b-Lacto, ß-lactoglobulin; BSA, bovine serum albumin; OVA, ovalbumin; HSA, human serum albumin; TNP, trinitrophenylated BSA.

 

View this table:
[in this window]
[in a new window]
  		Table II. Elevated Serum TABM
 


View larger version (27K):
[in this window]
[in a new window]
  		Figure 5. A model for the affect of TABM: antigen interaction on sensory neurons through TABM-associated TGF-ß. TABM-TGF-ß produced by T cells bind specifically to antigen and TABM-associated TGF-ß is thereby activated. The activated TGF-ß increases the production of substance P by sensory neurons and induces the production of TNF-{alpha} by monocytes that increases the entry of TABM into tissue by increasing vascular permeability.

 


   Footnotes
 
This work was supported by the National Institutes of Health (grant EY13243).

1 This manuscript is an update of a previously published Minireview entitled "Soluble T-Lymphocyte Antigen-Specific Immunoproteins: A Progress Report" (Proc Soc Exp Biol Med 2143:204–209, 1997). Back

2 To whom requests for reprints should be addressed at Department of Pathology, University of Connecticut Health Center, Farmington, CT 06030–3105. E-mail: cone{at}idx.uchc.edu Back


   References
Top
 Abstract
 Introduction
 Properties of Soluble Antigen...
 References
 

  1. Cone RE. Soluble extracellular antigen-specific T cell immunoproteins. J Leukocyte Biol 59:605–612, 1996.[Abstract]
  2. Cone RE. Soluble T-lymphocyte antigen-specific immunoproteins: a progress report. Proc Soc Exp Biol Med 214:204–209, 1997.[Medline]
  3. Cone RE, Little CH, Georgiou GM. T cell-derived antigen-specific serum proteins in infectious disease, melanoma, food intolerance and sensitivity to solvents: a central role in immune deviation, cytokine focusing and symptom production. Res Trends 3:131–144, 2000.
  4. Cone RE, Wang Y, O'Rourke J, Malley A. Extracellular (soluble) antigen-specific T cell proteins related to the T cell receptor for antigen (sTCRr): serologic and primary amino acid sequence similarity to T cell receptor {alpha}-chains and association with cytokines. J Interferon Cytokine Res 18:55–67, 1998.[Medline]
  5. Wang Y, O'Rourke J, Cone RE. Serum TABM produced during anterior chamber-associated immune deviation passively transfers suppression of delayed-type hypersensitivity to primed mice. Int Immunol 9:211–218, 1997.[Abstract/Free Full Text]
  6. Little CH, Georgiou G, Marceglia A, Ogedegbe H, Cone RE, Mazza D. Measurement of T-cell-derived antigen binding molecules and immunoglobulin G specific to Candida albicans mannan in sera of patients with recurrent vulvovaginal candidiasis. Infect Immun 68:3840–3847, 2000.[Abstract/Free Full Text]
  7. Kuchroo VK, Byrne MC, Atsumi Y, Greenfield E, Connonly JB, Whitters MM, Ohara R, Collins M, Dorf ME. T cell receptor {alpha} chain plays a critical role in antigen-specific suppressor cell function. Proc Natl Acad Sci U S A 88:8700–8705, 1991.[Abstract/Free Full Text]
  8. Griffith TS, Herndon JM, Lima J, Kahn M, Ferguson TA. The immune response and the eye. TCR {alpha}-chain related molecules regulate the systemic immunity to antigen presented in the eye. Int Immunol 7:1617–1625, 1995.[Abstract/Free Full Text]
  9. Fairchild RL, Palmer E, Moorhead JW. Production of DNP-specific/class I MHC-restricted suppressor molecules is linked to the expression of T cell receptor {alpha}- and ß-chain genes. J Immunol 150:67–77, 1993.[Abstract]
  10. Onda T, Brunner T, Messier H, Bissonnette R, Echeverri F, Baier G, Fotedar A, Green DR. Immunoregulatory activity of a T-cell receptor {alpha} chain demonstrated by in vitro transcription and translation. Proc Natl Acad Sci U S A 92:3004–3008, 1995.[Abstract/Free Full Text]
  11. Cone RE, Marchalonis JJ. Partial amino acid sequence of monoclonal extracellular antigen-specific T cell proteins. Immunol Invest 22:541–552, 1993.[Medline]
  12. Little CH, Georgiou GM, Fey G, Ravindran B, Levine J, Ogedegbe H, Yamase H, Cone RE. Detection of antigen-specific human serum proteins related to the T-cell receptor in infectious disease and in an immune response to milk proteins or chemicals. Proc Soc Exp Biol Med 224:264–272, 2000.[Abstract/Free Full Text]
  13. Shin J, Strominger JL. Translocation of TCR {alpha} chains into the lumen of the endoplasmic reticulum and their degradation. Science 259:1901–1903, 1995.
  14. DiBrino M, Ravindran B, Cone RE. T cell-derived proteins from normal human sera and their relationship to T cell antigen binding molecules. Clin Immunol Immunopathol 59:271–287, 1991.[Medline]
  15. Urbanski M, Cone RE. T cell-derived antigen specific humoral immune response. J Immunol 148:2840–2847, 1994.[Abstract]
  16. Urbanski M, Cone RE. T cell-derived antigen-specific humoral immune response. II. Further characterization of the response and the antigen-binding T cell immunoproteins. Cell Immunol 153:131–141, 1994.[Medline]
  17. Hadjikouti CA, Wang Y, O'Rourke J, Cone RE. Intracameral injection of antigen potentiates the production of antigen-specific T cell proteins in serum after the induction of delayed-type hypersensitivity. Invest Ophthalmol Vis Sci 36:1470–1476, 1995.[Abstract/Free Full Text]
  18. Streilein JW. Immune regulation and the eye: a dangerous compromise. FASEB J 1:199–208, 1987.[Abstract]
  19. Cone RE, Wang Y, O'Rourke J, Kosiewicz M, Okamoto S, Streilein JW. On the role of extracellular, antigen-specific T cell proteins in immune deviation elicited by intracameral soluble protein antigens. In: Nussenblatt RB, Whitcup SM, Caspi R, Gery I, Eds. Advances in Ocular Immunology. Amsterdam: Excerpta Medica, pp169–174, 1994.
  20. Wang Y, O'Rourke J, Cone RE. High-dose cyclophosphamide inhibits anterior chamber-associated immune deviation (ACAID) and the production of extracellular antigen-specific proteins induced by trinitrophenylated spleen cells. Cell Immunol 165:282–292, 1995.
  21. Wang Y, Goldschneider I, Foss D, Wu DY, O'Rourke J, Cone RE. Direct thymic involvement in anterior chamber-associated immune deviation: evidence for a nondeletional mechanism of centrally-induced tolerance to extrathymic antigen in adult mice. J Immunol 158:2150–2155, 1997.[Abstract]
  22. Kato K, Askenase PW. Reconstitution of an inactive antigen-specific suppressor factor by incubation of the factor with prostaglandins. J Immunol 133:2025–2031, 1984.[Abstract]
  23. Khalil Z, Georgiou GM, Ogedegbe H, Cone RE, Simpson F, Little CH. Immunological and in vivo neurological studies on a benzoic acid-specific T cell-derived antigen-binding molecule from the serum of a toluene-sensitive patient. Arch Environ Health 55:304–318, 2000.[Medline]
  24. Little CH, Georgiou G, Shelton MJ, Cone RE. Production of serum immunoglobulins and T-cell antigen binding molecules specific for cow's milk antigen in adults intolerant to cow's milk. Clin Immunol Immunopathol 89:160–170, 1998.[Medline]
  25. Xavier R, Nakamura M, Tsunematsu T. Isolation and characterization of a human non-specific suppressor factor from ascitic fluid of systemic lupus erythematosis. J Immunol 153:2624–2631, 1994.[Abstract]
  26. Bristow CL, Flood PM. T cell antigen receptor immune complexes demonstrating biologic and proteolytic activity. Int Immunol 5:79–88, 1993.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 CVIHome page
J. Kosonen, A. Rantala, C. H. Little, P. Lintu, P.-R. Harjamaki, G. M. Georgiou, R. E. Cone, and J. Savolainen
Increased Levels of Candida albicans Mannan-Specific T-Cell-Derived Antigen Binding Molecules in Patients with Invasive Candidiasis
Clin. Vaccine Immunol., April 1, 2006; 13(4): 467 - 474.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Cone, R. E.
Right arrow Articles by Little, C. H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Cone, R. E.
Right arrow Articles by Little, C. H.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS