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* Department of Microbiology and Immunology, School of Medicine, and
Genomic Research Center for Immune Disorders, Wonkwang University, Iksan, Chonbuk, Republic of Korea;
Vascular System Research Center and Department of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chunchon, Kangwon-Do, Republic of Korea; and
Seoul National University Medical School, Seoul, Republic of Korea
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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After the receipt of signals from APCs through TCR and CD28 costimulator, CD4+ T cells are triggered to produce IL-2 and enter the cell cycle. During or after several days of rapid cell division, these cells differentiate into one of two classes of effector CD4+ T cells (Th1 and Th2 cells). It is generally accepted that activation and subsequent proliferation of resting CD4+ T cells are essential processes in the T cell-mediated immune response and that they are associated with increased release of IL-2 (7).
The mitogen-activated protein (MAP) kinase cascade is one of the most ancient and evolutionarily conserved signaling pathways, which is also important for many processes occurring in immune responses. Three major groups of MAP kinases have been described in mammalian cells: they are the extracellular signal-regulated kinase (ERK), the Jun NH2-terminal kinase (JNK), and the p38 kinase (8). ERK, JNK, and p38 pathways are rapidly up-regulated by engagement of the TCR in T cells and play a critical role in the events leading to activation and increased IL-2 secretion (8). There are two isoforms of ERK, ERK-1 and -2. They can be activated by MAP/ERK kinase (MEK). ERK activation is dependent on p56lck and coupling of the TCR/CD3 complex to p21ras, with subsequent activation of the Raf-1/MEK/ERK kinase cascade (8, 9). JNK activation also requires p21ras and signals generated by the CD28 costimulatory receptor (10). The activation of the Raf-1/MEK/ERK pathway is essential for induction of IL-2 transcription in T cells (11). After phosphorylation of c-jun by JNK, activated c-fos and c-jun combine to form the AP-1 protein required for IL-2 synthesis (12). Interestingly, deficient ERK and JNK activations have been reported to exist in clones that are anergized (13). However, there is also evidence that ERK inhibition alone suppressed T cell proliferation, but did not induce anergy (14).
CO, a reaction product of HO-1 activity, has been shown to be highly protective in several rodent disease models (15, 16). It has anti-inflammatory, antiapoptotic, and antiproliferative effects (17), thereby conferring, at least in part, the protective effects of HO-1. Furthermore, the MAP kinase pathway has been shown to mediate the biological effects of CO: the p38 MAP kinase activation mediates the cytoprotective effect of CO on ischemia-reperfusion lung injury (18), CO prevents glucose deprivation-induced cytotoxicity through ERK MAP kinase inactivation in rat hepatocytes (19), and the antiproliferative effect of CO on smooth muscle cells and human airway smooth muscle cells requires p38 MAP kinase activation (20) and ERK MAP kinase inactivation (21), respectively.
We have recently demonstrated that human CD4+ T cells express HO-1 and that HO-1-overexpressing Jurkat T cells tend to display lower proliferative response (1). The aim of this study, therefore, was to elucidate the mechanism(s) by which HO-1 could mediate its antiproliferative effect on CD4+ T cells, and we demonstrated that CO, a reaction product of HO-1, could suppress IL-2 secretion, probably by inhibiting ERK activation, and thereby resulted in suppression of T cell proliferation in response to anti-CD3 plus anti-CD28 Abs.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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RPMI 1640 supplemented with 2 mM L-glutamine, 1% nonessential amino acids, 1% pyruvate, 100 U/ml penicillin, 100 µg/ml streptomycin (Life Technologies, Grand Island, NY), and 10% FBS (HyClone Laboratories, Logan, UT) was used as complete medium in all cultures. Anti-CD3 (clone UCHT1) and anti-CD28 (clone CD28.2) Abs were purchased from Immunotech (Westbrook, ME) and BD PharMingen (San Diego, CA), respectively. Phospho (p)-specific rabbit Abs to p-ERK-1/2, p-JNK-1/2, and p-p38 were obtained from Cell Signaling Technology (Beverly, MA), and ERK-1/2, JNK-1/2, and p38 Abs were from Santa Cruz Biotechnology (Santa Cruz, CA). PE- and FITC-conjugated and HRP-conjugated secondary Abs were purchased from BD PharMingen and Santa Cruz Biotechnology, respectively, and U0126 and cobalt protoporphyrin (CoPP) were from Promega (Madison, WI) and Porphyrin Products (Logan, UT), respectively. SP600125 was purchased from Calbiochem (San Diego, CA). CO gas (99%), tricarbonyldichlororuthenium (II) dimer (RuCO), SB203580, hemoglobin (Hb), and 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ) were purchased from Sigma-Aldrich (St. Louis, MO), and anti-HO-1 and anti-
-actin Abs were from Santa Cruz Biotechnology.cDNAs encoding constitutively active (S218E/S222E) and dominant negative (S218A/S222A) mutants of MEK1 were kindly provided by Dr. K. Y. Choi (Yonsei University, Seoul, Korea). HO-1 cDNA was a kind gift from Dr. A. M. K. Choi (University of Pittsburgh, Pittsburgh, PA). Recombinant human IL-2, IL-10, IFN-
, and anti-IL-10 neutralizing Ab were obtained from R&D Systems (Minneapolis, MN). CFSE was purchased from Molecular Probes (Eugene, OR). The other reagents were from Sigma-Aldrich.
Isolations of resting CD4+ T cells and CD8+ T cells from peripheral blood
PBMCs were isolated from healthy blood by Ficoll-Paque density gradient centrifugation. After three washes in HBSS, CD4+ T cells were isolated from PBMCs using the MACS negative depletion system (Miltenyi Biotec, Auburn, CA). No contamination with CD8+ T cells, B cells, monocytes, or NK cells was detected. Isolation of CD8+ cells was performed using a negative CD8+ T cell isolation kit (Miltenyi Biotec).
Cell transfection
HO-1, dominant-negative MEK1 (DN-MEK1), and constitutively active MEK1 (CA-MEK1) were cloned into pcDNA3 (Invitrogen, San Diego, CA). Jurkat T cells (5 x 106) were transfected with 10 µg of constructs by electroporation at 270V, 950 µF in serum-free RPMI 1640 using a Gene Pulser (Bio-Rad, Richmond, CA) followed by culture in RPMI 1640 supplemented with 10% FBS for 48 h and plating on 96-well plates at 5 x 105 cells/well in the presence of 1.25 mg/ml G418. Single stable clones of each transfectant were isolated and expanded.
CO exposure
T cells were exposed to compressed air or varying concentrations of CO (200 ppm), as previously described (22). Briefly, 1% CO in compressed air was mixed with compressed air with or without 5% CO2 in a stainless steel mixing cylinder before being delivered into the exposure chamber. The cell culture chamber was humidified and maintained at 37°C. A CO analyzer (CM-525HB; Gastec, Kanagawa, Japan) was used to monitor CO levels continuously in the chambers. T cells were grown in RPMI 1640 medium containing 10% FBS in a humidified atmosphere of 5% CO2 in air or 200 ppm CO and 5% CO2 in air.
T cell activation, cytokine analysis, and proliferation
The human acute T cell leukemia Jurkat clone E6-1 was obtained from the American Type Culture Collection (Rockville, MD). Purified CD4+ T cells or Jurkat T cells were cultured in RPMI 1640 supplemented with 10% heat-inactivated FBS at 37°C in 5% CO2. CD4+ T cells (2 x 105/well) were activated in flat-bottom, 96-well plates precoated with the anti-CD3 Ab (1 µg/ml) in the presence of soluble anti-CD28 Ab (1 µg/ml). CO gas, CO donor, CO scavenger, and ERK inhibitor at the appropriate concentrations were preincubated for 1 h before being added to plates and stimulated with anti-CD3 plus anti-CD28 Abs. Culture supernatants were harvested after 48 h of incubation for measurements of cytokine concentrations. Cytokine analysis was performed by analysis of supernatants with commercially available ELISA kits for human IL-2, IFN-, and IL-10 (R&D Systems). After 4 days of culture, proliferation wasassessed by [3H]TdR (0.5 µCi/well; Amersham Pharmacia Biotech, Piscataway, NJ) uptake for the next 16 h.
Evaluation of cGMP
Different pools of CD4+ T cell samples were incubated for 1 h at 37°C in the presence of 20 µM CO or air. To inhibit phosphodiesterase activity, 31-isobutyl-1-methyl xanthine (10 µM) was added to the cell suspension. The concentration of cGMP was determined by a radioimmunoassay kit using 125I-labeled cGMP (Amersham Pharmacia Biotech). Briefly, after incubation, 500 µl of 10% TCA was added to the cell suspensions. The samples were then centrifuged and TCA was extracted with 0.5 M tri-n-octylamine dissolved in TCA, and the samples were then acetylated with acetic anhydride and the amount of cGMP in the aqueous phase was measured.
Western blotting analysis
Cells were solubilized in ice-cold 1% Triton X-100 lysis buffer supplemented with protease and phosphatase inhibitors as described previously (21). After 30 min on ice, the lysates were clarified by centrifugation and the protein concentration was determined with the Pierce bicinchoninic acid protein assay reagent. Proteins (20 µg) were resolved by SDS-PAGE (10% acrylamide), transferred to nitrocellulose membranes, and probed with specific Abs (diluted 1/1,000), followed by incubation with secondary HRP-conjugated Ab (1/100,000). Bands were detected using the Luminol chemiluminescent detection reagents (New England Biolabs, Beverly, MA). Blots were exposed to autoradiographic film (DuPont Merk Chemistry Department, Wilmington, DE) for 1–2 min for detection.
Flow cytometry
Cells were suspended in HBSS containing 5% FBS, fixed by the drop-wise addition of ice-cold 70% ethanol to a final 50% concentration, and held on ice for 1 h. After extensive washing, the cells were suspended in HBSS containing 50 µg/ml propidium iodide (Sigma-Aldrich) and 50 µg/ml RNase A (Boehringer Mannheim, Indianapolis, IN) and were incubated for 1 h at room temperature. In some experiments, the states of ERK activation and HO-1 expression were determined by intracellular staining with either anti-p-ERK or anti-HO-1 Abs labeling either FITC- or PE-conjugated secondary Ab, as described previously (23). Stained cells were analyzed by flow cytometry on a FACSVantage with CellQuest software (BD Biosciences, Franklin Lakes, New Jersey). G0/G1, S, and G2/M populations were quantified using the ModFiT program (BD Biosciences).
CFSE dilution assay
Naive CD4+ T cells were labeled with 1.5 µM CFSE for 10 min at 37°C in serum-free RPMI 1640. Cells were washed twice in RPMI 1640 containing 10% FBS and were stimulated as indicated. Cell division was assessed at 4 days by determining the pattern of CFSE dilution using flow cytometry.
Statistics
Data were expressed as mean ± SEM of the individual titer. Levels of significant differences between groups were determined by the Student t test. Values of p <0.01 were considered statistically significant.
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Results |
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We found that pharmacological expression of HO-1 by the HO-1 inducer CoPP in PBMCs containing monocytes and lymphocytes was antiproliferative in response to anti-CD3 plus anti-CD28 Abs (Fig. 1A). This suggested that HO-1 expression in monocytes and/or lymphocytes could suppress T cell proliferation. Therefore, we examined whether CoPP could induce HO-1 expression in human CD4+ T cells purified from PBMCs and also whether HO-1 expression by CoPP could be antiproliferative. Preincubation of CD4+ T cells with CoPP for 12 h resulted in an apparent increase in HO-1 expression and a significant decrease in T cell proliferation (Fig. 1B). CoPP preincubation also suppressed the proliferative response of CD8+ T cells (data not shown). To further investigate the contribution of HO-1 expression to T cell proliferation, we transfected the HO-1 gene into human Jurkat T cells (Fig. 1C). In agreement with the CoPP data, overexpression of HO-1 suppressed T cell proliferation (Fig. 1C). These data demonstrate that HO-1 expression in T cells is antiproliferative.
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We next determined which of the HO-1 metabolites could mediate the antiproliferative effect of HO-1 on human CD4+ T cells. Thus, we preincubated CD4+ T cells with CO gas, bilirubin, or free iron (Fe2+) for 1 h before stimulation of the T cells with anti-CD3 plus anti-CD28 Abs. Only CO gas had an antiproliferative effect on CD4+ T cells (Fig. 2A). Similarly, the CO-releasing compound RuCO suppressed the proliferative response of CD4+ T cells in a dose-dependent manner (IC50 = 20 µM), but not in the presence of the CO scavenger Hb (Fig. 2B). In addition, a 12-h preincubation of CD4+ T cells with CoPP significantly suppressed the proliferative response, whereas a 12-h preincubation of the cells with CoPP in the presence of Hb showed no suppressive effect (Fig. 2C). Similarly, CoPP in the presence of Hb did not suppress the proliferation of either CD8+ T cells or Jurkat T cells (data not shown). CO gas, RuCO, CoPP, or Hb at concentrations used in these experiments showed no effect on T cell viability (data not shown). These results suggest that exogenous and endogenous CO can mimic the antiproliferative action of HO-1.
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We observed that addition of CO to CD4+ T cells 24 h after stimulation with anti-CD3 plus anti-CD28 Abs had no effect on proliferation (Fig. 3A). This suggested that CO was blocking early events leading to T cell activation. Therefore, we examined the effect of RuCO on the cell cycle and could show that CD4+ T cells did not progress past G0/G1 phase, if the cells were stimulated after preincubation with RuCO for 1 h (Fig. 3B, lower left panel). We could also show that CO was not inhibitory to cell cycle progression, if the activation was already progressed beyond TCR signaling (Fig. 3B, lower right panel). Furthermore, a kinetic CFSE analysis with intracellular HO-1 staining revealed that CO was not inhibitory to T cell cycle progression after a certain stage of activation because HO-1/CO was induced during T cell activation (Fig. 3C).
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CO inhibits IL-2 secretion by activated T cells, contributing antiproliferative effect of CO
IL-2 is an important regulator of T cell proliferation and is released by activated T cells (8, 9, 10, 11, 12, 13, 14). We observed that, among three HO-1 reaction products, only CO gas inhibited IL-2 secretion by activated CD4+ T cells (Fig. 4A). Similarly to CO gas, RuCO also inhibited the secretion of IL-2 by CD4+ T cells in a dose-dependent manner (IC50 = 20 µM), but not in the presence of Hb (Fig. 4B). Additionally, RuCO at higher concentrations reduced the secretion levels of IFN- and IL-10 (Table I). Moreover, preincubation of CD4+ T cells with CoPP inhibited IL-2 secretion, whereas preincubation with CoPP in the presence of Hb showed no inhibitory effect (Figs. 4C).
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nor IL-10 reversed the antiproliferative effects of CO (Fig. 4D). These data indicate that the suppression of T cell proliferation by CO could be due to its inhibition of IL-2 secretion. CO inhibits ERK phosphorylation in activated T cells, probably mediating the inhibitory effect of CO on IL-2 secretion
The ERK MAP kinases, which have been implicated as an intracellular target to contribute to certain CO-induced biological actions (19, 21), also play critical roles in T cell proliferation and IL-2 secretion (13, 14). Therefore, we examined the effects of CO gas and RuCO on ERK-1/ERK-2 activation in CD4+ T cells. CO gas and RuCO significantly inhibited ERK phosphorylation in the activated CD4+ T cells (Figs. 5, A and B). In contrast, RuCO had no effect on either p38 phosphorylation or JNK phosphorylation (Fig. 5B). In Jurkat T cells, RuCO also inhibited ERK phosphorylation in a dose-dependent manner (data not shown). Next, we were interested in determining the effects of blocking the ERK, p38, and JNK pathways on T cell proliferation. U0126, a selective inhibitor of ERK pathway, SB20358, a selective inhibitor of p38 pathway, and SP600125, a selective inhibitor of JNK pathway, were used to block each pathway. U0126 significantly suppressed T cell proliferation, but SB20358 and SP600125 did not (Fig. 5C). Suppression of T cell proliferation by U0126 was most likely due to reduction of IL-2 levels, because U0126-treated CD4+ T cells could proliferate when IL-2 was exogenously added to the cultures (Fig. 5C). In addition, RuCO at 20 µM reduced proliferative response even when p38 and JNK pathways were blocked by SB20358 and SP600125, respectively (Fig. 5C). However, RuCO did not further reduce T cell proliferative response when ERK pathway was effectively blocked by U0126 (Fig. 5C). These results further suggest that the ERK pathway might be involved in the suppressive effects of CO on T cell proliferation.
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Several studies have brought evidence that the intracellular signals that mediate activation of transcription factors regulating IL-2 gene transcription in human T cells involve p21ras-mediated signaling pathways (24, 25, 26, 27). These studies obtained with T cell lines collectively suggest that IL-2 gene transcription might require the p21ras/Raf-1/MEK/ERK phosphorylation cascade.
To further evaluate the role of the ERK pathway in CO-induced inhibition of IL-2 secretion, we transfected DN-MEK1 and CA-MEK1 genes into Jurkat T cells to selectively inhibit or activate the ERK1 pathway. DN-MEK1 expression suppressed ERK1 activation and IL-2 secretion by the simultaneous ligation of CD3 and CD28 Abs (Fig. 6), which was similar to RuCO effects on IL-2 secretion. Conversely, CA-MEK1 expression enhanced ERK1 activation and IL-2 secretion by the same stimuli (Fig. 6). No significant inhibition of IL-2 secretion by RuCO was observed in DN-MEK1- or CA-MEK1-transfected cells (Fig. 6). These results suggest that CO might block or inactivate upstream signaling cascades of MEK1, thereby inhibiting ERK pathway.
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It has been reported that IL-10 is able to induce HO-1 expression and to exert its anti-inflammatory effects via the HO-1-dependent pathway in monocytes (28). In human CD4+ T cells, IL-10 secretion (see Table I) as well as HO-1 expression (see Fig. 3C) was induced by the simultaneous ligation of CD3 and CD28 Abs. Thus, one may ask about whether IL-10 could be involved in HO-1 expression in CD4+ T cells. Although IL-10 itself did not induce HO-1 expression in naive CD4+ T cells, this cytokine further enhanced HO-1 expression in CD4+ T cells stimulated with CD3 plus CD28 Abs (Fig. 7). Moreover, anti-IL-10 neutralizing Ab reduced the level of HO-1 expression in activated CD4+ T cells (Fig. 7). It is most likely that there are many complex signals, including an IL-10 signal, to sufficiently induce HO-1 expression in human CD4+ T cells.
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Discussion |
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The exact mechanisms of HO-1 expression in activated T cells are currently unknown. However, the antiproliferative and anti-inflammatory IL-10 produced by activated CD4+ T cells was involved at least in part in HO-1 expression in T cells (Fig. 7), raising an interesting question of whether HO-1 expression could be involved in modulating T cell responses. Pharmacological induction or gene transfer of HO-1 in human T cells was antiproliferative (Fig. 1). Among the three HO-1 byproducts, only both exogenously added and endogenously generated CO-suppressed T cell proliferation (Fig. 2), mimicking the antiproliferative action of HO-1. Neither bilirubin nor free iron showed any effect on proliferative response under our experimental conditions. CO blocked the cell cycle entry of T cells, which was independent of guanylate cyclase/cGMP pathway (Fig. 3). However, it was of great interest to observe that CO was not inhibitory to cell cycle progression if the T cell activation already progressed beyond TCR signaling (Fig. 3, A–C). This suggests that CO blocks early events in T cell activation. CO also inhibited IL-2 secretion in CD4+ T cells stimulated with anti-CD3 plus anti-CD28 Abs (Fig. 4). This inhibitory effect of CO on the IL-2 secretion appears to be responsible for the antiproliferative action of CO, because T cell proliferation occurred when IL-2 was exogenously added to the culture (Fig. 4D). At high doses, CO also inhibited both IFN- and IL-10 secretions (Table I), but the additional inhibitions of these cytokines by CO were not associated with the antiproliferative effect of CO (Fig. 4D). MAP kinase plays an important role in IL-2 secretion, and there exists a strong correlation between decreased IL-2 secretion and the inhibition of ERK activation in T cells (13, 14). In support of these findings, our data clearly showed that CO selectively inhibited the ERK pathway in the activated T cells (Fig. 5). Furthermore, U0126, a selective inhibitor of ERK activation, suppressed T cell proliferative response, but not in the presence of exogenously added IL-2 (Fig. 5C). Similarly, an expression of DN-MEK1 inhibited IL-2 secretion (Fig. 6). These findings led us to suggest that CO might be able to inhibit the ERK activation, which leads to inhibition of IL-2 secretion, eventually resulting in suppression of T cell proliferation in response to the simultaneous ligation of CD3 and CD28 Abs.
Naive CD4+ T cells could be potentially exposed to endogenous CO produced by CD4+CD25+ regulatory T cells, which constitutively express HO-1 (1), as well as activated CD4+CD25− responder T cells, which can express HO-1 after stimulation. Thus, we speculate that CO may directly and/or indirectly affect T cell responses in vivo. It is of interest that CO shows cGMP-independent suppressive effects on T cell responses and it can inhibit ERK activation in activated CD4+ T cells. CO could indirectly inhibit ERK phosphorylation, probably by blocking upstream signals of MEK (Fig. 6). It could be possible that CO activates the small G protein, Rap1, which has been shown to inhibit ERK activation by blocking Ras-dependent activation of the MAP kinase kinase kinase, Raf-1 (32). Further studies are in progress to explore potential mechanisms of CO effects on ERK signaling pathways.
In summary, our findings suggest that HO-1/CO induces suppressive effects on T cell proliferation and IL-2 secretion, possibly via its inhibition of the ERK MAP kinase pathway, which is currently believed to be an important signaling pathway for mediating T cell activation. Our findings may contribute not only to our deeper understanding of the basic roles of HO-1 in the immune system, but also to our search for novel targets for new therapeutic approaches to modulate T cell-mediated immune responses.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Hun-Taeg Chung, Department of Microbiology and Immunology, Wonkwang University Medical School, 344-2 Shinyong-Dong, Iksan, Chonbuk 570-749, Republic of Korea. E-mail address: htchung{at}wonkwang.ac.kr
3 Abbreviations used in this paper: HO-1, heme oxygenase-1; MAP, mitogen-activated protein; ERK, extracellular signal-regulated kinase; JNK, Jun NH2-terminal kinase; MEK, MAP/ERK kinase; CoPP, cobalt protoporphyrin; RuCO, tricarbonyldichlororuthenium (II) dimer; Hb, hemoglobin; ODQ, 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one; DN-MEK1, dominant-negative MEK1; CA-MEK1, constitutively active MEK1.
Received for publication October 13, 2003. Accepted for publication January 23, 2004.
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12,14-prostaglandin J2. J. Biol. Chem. 278:19325.This article has been cited by other articles:
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 H. P. Kim, X. Wang, A. Nakao, S. I. Kim, N. Murase, M. E. Choi, S. W. Ryter, and A. M. K. Choi Caveolin-1 expression by means of p38{beta} mitogen-activated protein kinase mediates the antiproliferative effect of carbon monoxide PNAS, August 9, 2005; 102(32): 11319 - 11324. [Abstract] [Full Text] [PDF]
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K. Minamoto, H. Harada, V. N. Lama, M. A. Fedarau, and D. J. Pinsky Reciprocal regulation of airway rejection by the inducible gas-forming enzymes heme oxygenase and nitric oxide synthase J. Exp. Med., July 18, 2005; 202(2): 283 - 294. [Abstract] [Full Text] [PDF]
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S. Chen, M. H. Kapturczak, C. Wasserfall, O. Y. Glushakova, M. Campbell-Thompson, J. S. Deshane, R. Joseph, P. E. Cruz, W. W. Hauswirth, K. M. Madsen, et al. Interleukin 10 attenuates neointimal proliferation and inflammation in aortic allografts by a heme oxygenase-dependent pathway PNAS, May 17, 2005; 102(20): 7251 - 7256. [Abstract] [Full Text] [PDF]
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 P. O. Berberat, Z. Dambrauskas, A. Gulbinas, T. Giese, N. Giese, B. Kunzli, F. Autschbach, S. Meuer, M. W. Buchler, and H. Friess Inhibition of Heme Oxygenase-1 Increases Responsiveness of Pancreatic Cancer Cells to Anticancer Treatment Clin. Cancer Res., May 15, 2005; 11(10): 3790 - 3798. [Abstract] [Full Text] [PDF]
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H. Wang, S. S. Lee, W. Gao, E. Czismadia, J. McDaid, R. Ollinger, M. P. Soares, K. Yamashita, and F. H. Bach Donor Treatment With Carbon Monoxide Can Yield Islet Allograft Survival and Tolerance Diabetes, May 1, 2005; 54(5): 1400 - 1406. [Abstract] [Full Text] [PDF]
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T. M. Brusko, C. H. Wasserfall, A. Agarwal, M. H. Kapturczak, and M. A. Atkinson An Integral Role for Heme Oxygenase-1 and Carbon Monoxide in Maintaining Peripheral Tolerance by CD4+CD25+ Regulatory T Cells J. Immunol., May 1, 2005; 174(9): 5181 - 5186. [Abstract] [Full Text] [PDF]
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