A Molecular Basis for Bidirectional
Communication Between the Immune and Neuroendocrine Systems
J. EDWIN BLALOCK
Department of Physiology and Biophysics, University of Alabama at Birmingham,
A new interdisciplinary research area has recently emerged that involves the study of interactions between the immune and neuroendocrin
systems, which we term neuroimmunoendocrinology (73). Although this field was, in part, defined in 1977 (13), its origins are much earlier and may reside in an offshoot of the classic conditioning experiments of Pavlov (109). In 1926, Metal’nikov and Chorine (98) showed that, similar to many other physiological responses, immune reactions could be conditioned. The conclusion from these studies was that the central nervous system is involved in immune responses. More recently, these studies have been refined, confirmed, and extended by Ader and Cohen (for review, see Ref. 2). With the integration of the neurosciences and endocrinology and the development of the concept of stress came a possible explanation for one means by which the immune system might be regulated by the central nervous system (122). This explanation in part resided in Selye’s (123) observation of thymic involution during stress. Of course, the thymus is now recognized as an important organ for the maturation of lymphocytes, and adrenal glucocorticoids that are released during stress can have profound immunologic consequences. Today, although we recognize that the situation is not so simple as to involve only glucocorticoids, there are few who question that the neuroendocrine system can control immunologic functions. A less well accepted but perhaps more important recent advance in neuroimmunoendocrinology is the recognition that the immune system can regulate neuroendocrine functions. Observations related to this later concept have begun to provide a biochemical basis for what we now understand is bidirectional, rather than unidirectional, communication between the immune and neuroendocrine systems. Such bidirectional communication is the subject of this review.
II. CELLULAR COMPONENTS OF THE IMMUNE SYSTEM
The immune system, like the neuroendocrine system, is composed of a number of specialized cell types that have unique functions and particular sets of chemical messengers. In general, these cells are typed according to their function and their immunologically defined cell surface markers (Table 1). It should be noted that cell surface markers are described for the mouse but equivalent structures are found in humans. The following is a brief and general overview of a number of the major cell types in the immune system (for a more detailed review, see Ref. 79).
A. T Lymphocytes
These cells represent one of two major classes of lymphocytes and derive their name from the fact that they and their precursors spend time in the thymus. A marker on all T-cells is the 0-antigen or Thy-1 that interestingly enough was originally found on brain tissue. The two main functions of these cells are destruction of host cells with altered (or nonself) surfaces and regulation of immune reactions. The latter function can occur either by direct
table 1. Cellular components of the immune system
|Cell Type||Antigenic Markers||Immunologic Functions||Soluble Mediators|
|Th lymphocytes||Thy-1+, Lyt-1+, Lyt-2″||Augmentation of immunologic reactions||IL2|
|T8/c lymphocyte||Thy-1+, Lyt-1+/“, Lyt-2+||Suppression of immunologic reactions, mediate cell killing||IFN-7|
|NK cells||Thy-1+/“, NK 1+||Killing of virus-infected and tumor cells||IFN-a|
|B lymphocytes||Ig+||Production of antibody||Ig, IFN-a|
|Macrophages||MAC1+||Phagocytosis and killing of infectious agents, antigen processing and presentation||IL 1, IFN-a|
See text for definitions of abbreviations.
interaction with other cells or indirectly through the production and release of soluble mediators that, as we will see, were probably misnamed lympho-kines. Cells that fulfill the above two functions are also characterized by cell surface antigens of the Lyt series, which include Lyt-1 and Lyt-2. Most T lymphocytes that augment immunologic reactions are called helper cells (Th) and are Lyt-1+ Lyt-2~. Cytotoxic (Tc) and suppressor (Ts) cells are generally Lyt-1″1 Lyt-2+ or Lyt-1+ (lower density than Th) Lyt-2+. T lymphocytes that are not fully differentiated are also Lyt-1+ Lyt-2+.
T lymphocytes are responsive to T-cell mitogens such as concanavalin A (ConA), phytohemagglutinin (PHA), and staphylococcal enterotoxin A (SEA). On interaction with T-cell mitogens, at least two events occur. T lymphocytes undergo a blastogenic response that is commonly measured by incorporation of [3H]thymidine into DNA, and they produce lymphokines. Among the more prominent lymphokines are interleukin 2 (IL 2) and 7-in-terferon (IFN-7). Interleukin 2 promotes and maintains the growth of T lymphocytes, whereas IFN-7 activates cytotoxic cells and macrophages, increases the expression of antigens of the major histocompatability complex, and inhibits virus infection.
B. B Lymphocytes
The second major class of lymphocytes is termed B-cells, and the name refers to bursa derived in avian species and bursa equivalent or bone marrow derived in mammals. The primary marker for B lymphocytes is the cyto-plasmic (c) or cell surface (s) expression of immunoglobulin (Ig). Pre-B-cells
are characterized by the presence of clgM, whereas virgin B lymphocytes express both clgM and slgM. Ultimately, B lymphocytes progress through various patterns of heavy chain switching to antibody-forming cells that express only one Ig class (E, A, G, M, or D) both cytoplasmically and on their surface. The main function of these cells is the synthesis of Ig. The B lymphocytes are responsive to B-cell mitogens such as bacterial lipopolysaccha-ride (LPS) and, like T-cells, respond with a blastogenic response. In addition, they can synthesize and secrete Ig and IFN-a as a result of the mitogenic signal.
C. Natural Killer Cells
Natural killer (NK) cells are large granular lymphocytes that lack the major cell surface markers that are generally associated with T and B lymphocytes. They do, however, have a low density of Thy-1, which indicates they may be of T-cell lineage. The principal functions of NK cells are the killing of virus-infected and tumor cells in the absence of prior sensitization. They are further characterized by the presence of a cell surface molecule termed NK 1. The predominant lymphokine that is produced by these cells is IFN-a. Among its many effects, IFN-a is inhibitory for virus replication, enhances NK cell activity, and elevates expression of antigens of the major histocom-patability complex.
The differentiation phase of monocyte development occurs in the bone marrow from which maturing monocytes enter the blood. From the peripheral circulation, monocytes enter various tissues and transform into macro-phages. There are two types of macrophages: one is migratory and moves from tissue to tissue, and the other is called a histiocyte and remains fixed within a particular tissue site. Hallmarks of macrophages are their adherence to surfaces and ability to phagocytize. They bear a characteristic cell surface marker called Mac 1 and participate in many immunologic functions. Among these are phagocytosis of foreign material, such as bacteria, antigen processing and presentation for Ig synthesis, and involvement in delayed-type hypersensitivities and tumor immunity. Immunologic substances that are secreted by macrophages include complement components, IFN-a, and the monokine IL 1. The classic action of IL 1 is the ability to induce IL 2 and drive thymocyte proliferation.
These cells are also known as polymorphonuclear (PMN) leukocytes. The three types of mature granulocytes, neutrophils, eosinophils, and basophils,
are distinguished based on their color when reacted with Giemsa stain. Tissue-bound basophils are known as mast cells. The main function of neutro-phils is the phagocytosis and killing of bacteria and other infectious agents. Basophils are involved in anaphylactic and allergic (immediate type hyper-sensitivity) reactions as well as immunity to parasites.
III. IN VITRO IMMUNOREGULATORY FUNCTIONS OF NEUROENDOCRINE PEPTIDE HORMONES
Until recently, most interactions between the immune and neuroendo-crine system were attributed to glucocorticoid hormones. Now, however, we are beginning to recognize that peptide hormones can directly modulate immune responses (Table 2). Such is the case even for hormones such as adrenocorticotropic hormone (ACTH) that were previously thought to act almost exclusively through glucocorticoids. Although steroid hormones are clearly important players in immunoregulation (38, 39), the focus of this review concerns peptide hormones.
A. Adrenocorticotropic Hormone
Adrenocorticotropic hormone has been found to regulate the functions of most of the major types of cells within the immune system. For instance, in an in vitro plaque-forming cell (PFC) assay that measures antibody-secreting cells, ACTH-(1—39) suppressed the response to both a T-cell-dependent antigen, sheep red blood cells (SRBC), and a T lymphocyte-independent antigen, dinitrophenol (DNP)-Ficoll (73). Inhibition of PFC to SRBC required only one-quarter of the amount of ACTH for equal inhibition of the DNP-Ficoll response. Because the SRBC response is dependent on T-cells, this lower dosage suggests that the T-cell requirement may be more sensitive to ACTH than B-cell function. Although these studies were done with micro-molar amounts of ACTH that are clearly not physiological, this high effective dose was due to adding ACTH as a bolus on day 0 and measuring the PFC response 5 days later. By the daily addition of ACTH, the amount required could be reduced to a subnanomolar concentration (unpublished results). Interestingly, ACTH-(1—39) was suppressive and ACTH-(1—24) was not. This is in contrast to the steroidogenic activity of ACTH, where both forms are equally active (93). On the surface, this might indicate that the effect is mediated through the COOH-terminus of the peptide. However, this is not the case, since ACTH-(18—39) was not suppressive. As is discussed (sect. mi?), this appears to be a recurrent theme in immunoregulation by peptide hormones. That is, cellular components of the immune system can distinguish between closely related or truncated peptides, whereas the classic neu-roendocrine target cell may not. Although different receptors or binding sites would be the simplest explanation, this is not necessarily the case, since
TABLE 2. Immunoregulatary effects of neuroendocrine peptides
Leu- or Met-enkephalin
AVP and oxytocin
Suppression of Ig and IFN-7 synthesis 73, 75
Augmentation of B-cell proliferation 4, 26
Suppression of IFN-7-mediated macrophage activation 80
Suppression of Ig synthesis and secretion 70, 73
Suppression of antigen-specific T-cell helper factor 70
Enhancement of Ig and IFN-7 synthesis 31, 69, 92
Modulation of T-cell proliferation 59, 95
Enhancement of generation of Tc-cells 36
Enhancement of NK cell activity 48, 54, 76, 92, 94
Chemotactic for monocytes and neutrophils 29,119,120,141
Suppression of Ig synthesis 73
Enhancement of IFN-7 synthesis 31
Enhancement of NK cell activity 48, 76
Chemotactic for monocytes 119,120,141
Enhancement of Ig synthesis 18, 84
Enhancment of generation of Tc-cells 133,137
Replacement of IL 2 requirement for IFN-7 synthesis 74
Augmentation of T-cell proliferation 60, 111
Degranulation of mast cells and basophils 60
Enhancement of macrophage phagocytosis 111
Elicitation of O2, H202, and thromboxane B2 production 111
Suppression of histamine and leukotriene D4 release 60, 111
Suppression of T-cell proliferation 60, 111
Suppression of Tc and NK cell activity 3
Suppression of T-cell proliferation 116
Suppression of mixed lymphocyte reactions 116
Generation of Ts-cells 55
See text for definitions of abbreviations.
in some instances the same receptor is probably involved (see sect. mi?). Thus one of the future challenges will be to determine the mechanisms by which such discrimination occurs. For maximal inhibition of antibody synthesis, it was necessary for ACTH-(1—39) to be present at the time of antigen addition, and thiol-reducing agents blocked the ACTH-mediated effect. Because these characteristics are associated with suppression of antibody by IFN-a and IFN-/8, it seems that the mechanisms or intracellular site through which ACTH inhibits the antibody response may be quite similar to that of a lymphokine, IFN (73).
In addition to antibody synthesis, B-cell proliferation is another B lymphocyte response that is modulated by ACTH. Brooks et al. (27) demon-
strated a small, B-cell-derived B-cell growth factor (BCGF) that was secreted by a B lymphoblastoid cell line (BGLx) and that was involved in the prolifer-ative response of these cells. This BCGF was suggested to be a product of pro-opiomelanocortin (POMC) mRNA that was expressed by these cells. Subsequently, Bost et al. (26) showed that BCLi cells produce ACTH and harbor an ACTH receptor. They further suggested that this hormone might be an autocrine growth factor for these cells. Similarly, Alvarez-Mon et al. (4) found that pituitary-derived ACTH could enhance the growth and differentiation of normal B lymphocytes when added in conjunction with large-molecular-weight BCGF or IL 2. On the surface, these results might seem surprising, since ACTH suppressed antibody production. However, it may be that in the antibody production system the block is at the conversion to the plasmacyte stage, whereas the ACTH-enhanced proliferation results from an action on an earlier cell in the B lymphocyte lineage.
The T-cell and macrophage functions are also modulated by ACTH. For instance, this hormone suppressed in vitro lymphokine, IFN-7, production (75) by T lymphocytes. The peptide structural requirements for this effect were essentially those observed for regulation of antibody production. Both natural and synthetic ACTH-(1—39) suppressed the induction of IFN-7, whereas ACTH-(l-24), ACTH-(18-39), and acetyl ACTH-(1-13) amide [a-melanocyte-stimulating hormone (a-MSH)] did not. Once again, there seemed to be no correlation between the steroidogenic and immunoregula-tory properties of these peptides. In addition to blocking the T-cell production of IFN-7, ACTH completely blocked the ability of preformed IFN-7 to activate macrophages to a tumoricidal state (80). Thus ACTH is able to modulate the function of at least three of the principal cells within the immune system: T-cells, B-cells, and macrophages.
B. Endorphins and Enkephalins
The endogenous opioid peptides are also able to influence the functions of most of the major cell types within the immune system. An interesting aspect of the immunoregulatory activity of endorphins is that even though the a-, 7-, and j8-forms have identical NH2-termini, they have different im-munomodulatory functions (128). For instance, Johnson et al. (73) showed that a-endorphin, as well as Met- and Leu-enkephalins but not /?- or 7-en-dorphins, were potent suppressors of antibody production. Although one might think that this effect was initiated by the COOH-termini of these peptides, this was not the case, since naloxone (an opiate antagonist) and j8-endorphin blocked the suppressive activity of a-endorphin. This later finding would suggest a “classic” opiate receptor was involved. Heijnen et al. (70) recently investigated the mechanism of a-endorphin suppression of antibody production and found that at least three processes were involved. First, a-endorphin blocked the production and/or secretion of an antigen-specific
T-cell helper factor for antibody production; second, it blocked the secretion of antibody; and third, it inhibited the transition of B-cells into more mature PFC. Although Johnson et al. (73) initially found that /3-endorphin did not affect antibody production, Heijnen and Ballieux (69) found that by the appropriate timing of addition, it enhanced the number of antibody-forming cells, and this effect was initiated by the COOH-terminal end of the peptide. Thus this is a most interesting situation where there is the potential for two opposing actions of opposite ends of the same peptide.
With regard to T lymphocytes, the first reported effect of an opioid peptide was the observation that Met-enkephalin increased the percentage of T-cells that formed active rosettes with SRBC (145). Others have confirmed the initial observation and extended it to include Leu-enkephalin (100-102). In contrast to the enhancing effect that enkephalins have on active rosette formation (short incubation, low SRBC-to-T-cell ratio), these opioids depress total T-cell rosette formation (long incubations, optimal SRBC-to-T-cell ratio). The significance of altered rosetting of T lymphocytes with SRBC is not yet clear, although kinetic studies utilizing morphine, an opioid receptor agonist, indicate that suppressed rosetting may be due to changes in membrane fluidity and altered receptor cycling (44).
As mentioned in section n, lymphocyte proliferation is an often used parameter of immune function. In response to stimulation with mitogenic lectins, the uptake of isotopically labeled nucleotides such as [3H]thymidine can easily be measured and is an indirect indication of proliferation. The effect can be lymphocyte-subtype (T vs. B) specific depending on the mitogen. Interestingly, /?-endorphin, but neither of its NH2-terminal peptides a-en-dorphin or Met-enkephalin, enhanced the proliferative response of rat splenocytes to the T-cell mitogens ConA and PHA but not to the B-cell mitogens LPS and dextran sulfate (59). The opiate receptor antagonist, nal-oxone, failed to prevent the enhanced response, suggesting that /?-endorphin was acting at a specific nonopiate receptor for £-endorphin not unlike that described for its COOH-terminus by Hazum et al. (68). Human peripheral blood lymphocytes exhibited an entirely different response to /?-endorphin. The proliferative response of these cells to ConA was significantly depressed by 0-endorphin (95), an effect that also could not be prevented by naloxone. At present, we do not know whether the diametrically opposed actions of the COOH-terminus of /?-endorphin on T-cell mitogenesis are due to different species, different tissues of lymphocyte origin, or different concentrations of peptide employed by a particular investigator. The last possibility seems a distinct one, since many peptides have been shown to have opposing immuno-logic effects depending on the concentration.
Another important endogenous opioid-regulated lymphocyte function is cytotoxic activity against foreign or altered host cells. Opioid peptides enhanced the generation of cytotoxic T lymphocytes (36) as well as the expression of NK cell-mediated cytotoxicity (48,54,76,92,94). Because both of these effector cell functions are upregulated by IFN-7, it is tempting to speculate
that they might result from the ability of /3-endorphin and Met-enkephalin to enhance IFN-7 production by human peripheral blood lymphocytes (31) and NK cells (92). On the other hand, the production of another lymphokine that is chemotactic for T lymphocytes is suppressed by /?-endorphin and Met-enkephalin (30). Although opioid peptides suppress the production of a T-cell chemotactic factor, they stimulate chemotaxis of monocytes and neutrophils both in vivo and in vitro (29, 119, 120, 141). Thus, as was seen with ACTH, endogenous opioid peptides can modulate the functions of each of the major types of leukocytes.
Although thyrotropin (TSH) was one of the first neuroendocrine hormones that was recognized to play an important role in immunologic regulation in vivo (112), its effects on leukocytes in vitro are apparently limited to studies of antibody production. Thyrotropin enhanced the in vitro antibody response at physiological concentrations (18, 84). Specific cell-depletion studies showed that the TSH enhancement, although independent of macro-phages, required the presence of T lymphocytes (84). Because an antibody is a B lymphocyte product and yet the enhancement required T-cells, these data showed that the effect of TSH on antibody production was indirectly mediated through an action on T-cells.
Interestingly, TSH is a pituitary hormone that can be produced by lymphocytes in response to thyrotropin-releasing hormone (TRH; see sect, v), and TRH, like TSH, enhanced the in vitro antibody response. This enhancement was not observed with growth hormone-releasing hormone (GHRH), arginine vasopressin (AVP), or luteinizing hormone-releasing hormone (LHRH) and was blocked by antibodies to the 0-subunit of TSH (T. E. Kruger, L. R. Smith, D. V. Harbour, and J. E. Blalock, unpublished results). Thus it appears that TRH specifically enhances the in vitro antibody response via production of TSH (Fig. 1). This finding seems particularly important in that it is the first demonstration that a neuroendocrine hormone (TSH) can function as an endogenous regulator within the immune system.
D. Growth Hormone
Growth hormone is another pituitary protein that was initially recognized as having profound in vivo effects on the immune system. For instance, in addition to having very low levels of GH, dwarf mice have very depressed immunologic responses and involuted central and peripheral lymphatic tissue (5). Particularly affected is the thymus, and hence it is not surprising that T lymphocyte-dependent immune responses are especially deficient (112, 113). An apparent in vitro correlate of the above is the finding that in
|| Immunoglobulin Synthesis
media with a serum substitute, insulin but not GH was sufficient to enable T-cell proliferation in a murine one-way mixed lymphocyte reaction (133). However, GH was required by insulin-treated T lymphocytes for the enhanced generation of functional cytotoxic T-cells (133). In a similar study that employed human rather than murine lymphocytes, a combination of insulin and GH was shown to enhance the level of T-cell growth (137). Collectively, these results suggest that GH may influence both the proliferation of T lymphocytes as well as their terminal differentiation into effector cells.
Thyrotropin Releasing Hormone
3T<—T3 or T4
fig. 1. A model for thyrotropin-releasing hormone (TRH) enhancement of antibody synthesis. TRH causes triiodothyronine (T3)- or thyroxine (T4)-suppressible synthesis of thyrotropin (TSH) by T lymphocytes. TSH in turn activates a T lymphocyte by a mechanism that is inhibitable by antibody to #-chain of TSH. Activated T-cell then acts on a B lymphocyte to elevate immunoglobulin synthesis. Activated T-cell can be eliminated with antibody to the 0-antigen.
E. Arginine Vasopressin and Oxytocin
-y-Interferon production is regulated by an interaction of T lymphocyte subtypes and involves Th, Ts, and IFN-7 producer cells. The Th cell requirement for IFN-7 production is solely mediated by its product IL 2, which acts on the IFN-7 producer cell (for review, see Ref. 74). Interestingly, in this system, Johnson and Torres (74) showed that AVP at subnanomolar concentrations could completely replace the requirement for IL 2 (74). Unlike IL 2, however, AVP neither induced thymocyte proliferation nor acted cooperatively with T-cell mitogens. Thus AVP could fulfill one but not all of the functions of IL 2. Structure/function was most likely mediated by the six NH2-terminal amino acids with the phenylalanine at position three being of particular importance. Furthermore, a competitive inhibitor of the vaso-pressor effect of AVP also blocked its immunologic activity (74). This suggested that the AVP receptor on lymphocytes may be similar to the vaso-pressor type. Oxytocin had IFN-7 regulatory effects that were very similar to AVP, albeit at a 10-fold higher concentration.
F. Substance P
Peptides of the peripheral nervous system, such as substance P and somatostatin, seem to be major players in the expression and modulation of immediate-type hypersensitivity reactions (for review, see Ref* 60). Such effects are, in part, mediated through their ability to evoke and/or regulate a noncytotoxic degranulation of mast cells and basophils. For instance, at physiologically relevant concentrations, somatostatin and substance P cause rapid histamine release from rat serosal mast cells. Cellular specificity can be demonstrated by the greater potency of substance P in activating mucosal than connective tissue mast cells. That a unique mechanism of mast cell activation was involved was suggested by the ability of substance P and somatostatin to stimulate histamine release from mast cells that were previously desensitized to other stimuli by treatment with IgE and antigen or the mast cell-activating fifth component of complement. In contrast to tissue mast cells, basophils in the circulation do not release mediators in response to sensory neuropeptides. However, nanomolar to subpicomolar concentrations of somatostatin were able to suppress IgE-mediated histamine and leukotriene D4 release from human basophils (60). Thus certain sensory neuropeptides would seem to have the ability to elicit immediate-type hypersensitivity at local tissue sites and perhaps suppress such reactions in the peripheral circulation.
In addition to regulating components of immediate-type hypersensitivity, substance P and somatostatin can modulate cells that are involved in delayed-type hypersensitivity reactions and cell-mediated immunity (for review, see Ref. 111). At nanomolar concentrations, substance P is known to increase the phagocytosis of yeast cells by mouse macrophages or human PMN leukocytes. Although the phagocytosis-enhancing ability of this neuro-peptide resides in the NH2-terminal tetrapeptide, the COOH-terminal portion of substance P appears to be responsible for stimulation of PMN leukocyte chemotaxis in vitro. Substance P also evoked 02 and H202 production by activated guinea pig peritoneal macrophages and caused thromboxane B2 liberation. T lymphocytes are also affected by sensory neuropeptides, and substance P and somatostatin can have opposite effects. For instance, substance P can increase [3H]thymidine and leucine uptake by T^cells in the presence or absence of mitogens, whereas somatostatin has an opposite effect.
G. Vasoactive Intestinal Peptide
Vasoactive intestinal peptide (VIP) is perhaps the best-studied immu-noregulatory neuroendocrine peptide with regard to its putative molecular mode of action on lymphocytes. This peptide has been shown to inhibit the
mitogen-induced proliferative response of T but not B lymphocytes (108). Furthermore, T but not B lymphocytes seem to possess a VIP receptor (107). Such suppression is preceded by binding of this ligand to a VIP receptor and subsequent activation of adenylate cyclase. In a T-cell line (MOLT 4b), this leads to cAMP-dependent protein kinase-mediated phosphorylation of a MOLT 4b protein of a molecular weight of 41,000. O’Dorisio et al. (for review, see Ref. 105) have suggested that such VIP-mediated phosphorylation may induce synthesis and release of a suppressor factor that inhibits lymphocyte mitogenic responses. Another immunoregulatory function of VIP is modulation of lymphocyte migration. Vasoactive intestinal peptide was shown to inhibit the egress of small lymphocytes out of popliteal lymph nodes, while downregulation of VIP receptors on T-cells decreased the ability of these cells to migrate into mesenteric lymph nodes (106). These results suggest the interesting possibility that specific neuroendocrine peptide receptors may determine the tissue location of particular subsets of lymphocytes.
H. Human Chorionic Gonadotropin
Current models of pregnancy suggest that maternal immunologic recognition of the blastocyst and production of effector factors that mediate suppression of subsequent immune responses are necessary components of successful pregnancy (37). Interestingly, chorionic gonadotropin (CG) could be one such suppressor factor, since it has been shown to inhibit cytotoxic T-cell and NK cell activity, T-cell mitogenesis, and mixed lymphocyte reactions (3, 7, 55,116). One mechanism for this effect might be through the ability of CG to induce suppressor cell activity (55). Siiteri et al. (125) have suggested that immunosuppression by CG may in part be indirectly mediated through progesterone secretion that is directly immunosuppressive (125).
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