scholarly journals The relationship between human thymus-derived regulatory T cells, TGF-β-induced regulatory T cells and conventional CD4+ T cells as revealed by proteomics

2021 ◽  
Author(s):  
Mark Mensink ◽  
Ellen Schrama ◽  
Maartje van den Biggelaar ◽  
Derk Amsen ◽  
Jannie Borst ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Protein Expression ◽  
Treg Cell ◽  
Ex Vivo ◽  
Foxp3 Expression ◽  
Treg Cells ◽  
Cell Populations ◽  
The Relationship

The CD4+ regulatory T (Treg) cell lineage, as defined by FOXP3 expression, comprises thymus-derived (t)Treg cells and peripherally induced (p)Treg cells. In human, naive tTreg cells can be purified from blood, but occur in low abundance, while effector pTreg and tTreg cell populations cannot be purified for lack of discriminating cell surface markers. Therefore, studies often employ TGF-β-induced (i)Treg cells that are generated from CD4+ conventional T (Tconv) cells in vitro. Here, we describe the relationship of iTreg cells to tTreg and Tconv cells, as optimally purified from human blood. Global proteomic analysis revealed that iTreg, tTreg and Tconv cell populations each have a unique protein expression pattern. We next used as a benchmark a previously defined proteomic signature that discerns ex vivo naive and effector phenotype Treg cells from Tconv cells and reflects unique Treg cell properties. This Treg cell core signature was largely absent from iTreg cells, while clearly present in simultaneously analyzed tTreg cells. In addition, we used a proteomic signature that distinguishes ex vivo effector Treg cells from Tconv cells and naive Treg cells. This effector Treg cell signature was partially present in iTreg cells. Thus, iTreg cells are distinct from tTreg cells and largely lack the common Treg cell proteomic signature. However, they do have certain protein expression features in common with ex vivo effector Treg cells. These data demonstrate the utility of the core and effector Treg cell signatures as tools to define Treg cell populations and encourage the use of ex vivo Treg cells for functional analyses.

scholarly journals FOXP3 expression accurately defines the population of intratumoral regulatory T cells that selectively accumulate in metastatic melanoma lesions

Blood ◽  
2008 ◽  
Vol 112 (13) ◽  
pp. 4953-4960 ◽  
Author(s):  
Mojgan Ahmadzadeh ◽  
Aloisio Felipe-Silva ◽  
Bianca Heemskerk ◽  
Daniel J. Powell ◽  
John R. Wunderlich ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Metastatic Melanoma ◽  
Treg Cell ◽  
Peripheral Blood ◽  
Ex Vivo ◽  
Production Capacity ◽  
Biological Marker ◽  
Foxp3 Expression ◽  
Treg Cells

Abstract Regulatory T (Treg) cells are often found in human tumors; however, their functional characteristics have been difficult to evaluate due to low cell numbers and the inability to adequately distinguish between activated and Treg cell populations. Using a novel approach, we examined the intracellular cytokine production capacity of tumor-infiltrating T cells in the single-cell suspensions of enzymatically digested tumors to differentiate Treg cells from effector T cells. Similar to Treg cells in the peripheral blood of healthy individuals, tumor-infiltrating FOXP3+CD4 T cells, unlike FOXP3− T cells, were unable to produce IL-2 and IFN-γ upon ex vivo stimulation, indicating that FOXP3 expression is a valid biological marker for human Treg cells even in the tumor microenvironment. Accordingly, we enumerated FOXP3+CD4 Treg cells in intratumoral and peritumoral sections of metastatic melanoma tumors and found a significant increase in proportion of FOXP3+CD4 Treg cells in the intratumoral compared with peritumoral areas. Moreover, their frequencies were 3- to 5-fold higher in tumors than in peripheral blood from the same patients or healthy donors, respectively. These findings demonstrate that the tumor-infiltrating CD4 Treg cell population is accurately depicted by FOXP3 expression, they selectively accumulate in tumors, and their frequency in peripheral blood does not properly reflect tumor microenvironment.

scholarly journals Androgen receptor modulates Foxp3 expression in CD4+CD25+Foxp3+ regulatory T-cells

2015 ◽  
Vol 26 (15) ◽  
pp. 2845-2857 ◽  
Author(s):  
Magdalena Walecki ◽  
Florian Eisel ◽  
Jörg Klug ◽  
Nelli Baal ◽  
Agnieszka Paradowska-Dogan ◽  
...  
Keyword(s):  
T Cells ◽  
Androgen Receptor ◽  
Treg Cell ◽  
Foxp3 Expression ◽  
Treg Cells ◽  
Strong Increase ◽  
Histone H4 ◽  
And Function

CD4+CD25+Foxp3+ regulatory T (Treg) cells are able to inhibit proliferation and cytokine production in effector T-cells and play a major role in immune responses and prevention of autoimmune disease. A master regulator of Treg cell development and function is the transcription factor Foxp3. Several cytokines, such as TGF-β and IL-2, are known to regulate Foxp3 expression as well as methylation of the Foxp3 locus. We demonstrated previously that testosterone treatment induces a strong increase in the Treg cell population both in vivo and in vitro. Therefore we sought to investigate the direct effect of androgens on expression and regulation of Foxp3. We show a significant androgen-dependent increase of Foxp3 expression in human T-cells from women in the ovulatory phase of the menstrual cycle but not from men and identify a functional androgen response element within the Foxp3 locus. Binding of androgen receptor leads to changes in the acetylation status of histone H4, whereas methylation of defined CpG regions in the Foxp3 gene is unaffected. Our results provide novel evidence for a modulatory role of androgens in the differentiation of Treg cells.

Unique Role of mTOR Inhibitor, Everolimus in Inducible Regulatory T Cells

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4349-4349
Author(s):  
Tokiko Nagamura-Inoue ◽  
Yuki Yamamoto ◽  
Seiichiro Kobayashi ◽  
Kazuo Ogami ◽  
Kiyoko Izawa ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Cd4 T Cells ◽  
Mtor Inhibitor ◽  
Conflicts Of Interest ◽  
Ex Vivo ◽  
Foxp3 Expression ◽  
Induction Rate ◽  
The Impact

Abstract Abstract 4349 Background: Regulatory T cells (Tregs) play an important role in immune-tolerance to allograft. Unbalance between Tregs and effector T cells is involved in graft-versus-host disease (GvHD) and other autoimmune disorders. Adoptive use of inducible Tregs (iTregs) is a candidate immunosuppressive therapy, and major concern has been focused on sustained expression of Foxp3 in iTregs. We previously reported that iTregs can be efficiently expanded from cord blood (CB)-derived CD4+ T cells in the presence of IL2, TGFb and a mTOR inhibitor, Everolimus (Eve). However, the effect of Eve on in vitro induction of iTreg remains to be elucidated. Here we studied the impact of Eve on CB-CD4+ T cells. Methods: CD4+ T cells were prepared from CB with a purity of >95% and put into the flask coated with anti-CD3/CD28 MAb. For Treg induction, these cultures were supplemented with IL2, IL-2/TGFb, IL2/TGFb/Eve, or IL2/Eve and kept for two weeks. The resulting CD4+ T cells including variable proportion of iTregs were subjected to mixed lymphocyte reaction (MLR) along with CFSE-labeled autologous responder T cells and allogeneic dendritic cells (DCs) as stimulator. Results: The basal proportion of CD25+Foxp3+ cells in CB-CD4+ T cells was 0.60 ± 0.59%. After two weeks, the induction rate of CD25+Foxp3+CD4+ T cells was higher in the culture with IL2/TGFb/Eve than that with IL2/TGFb, but Eve itself could not significantly induce iTregs in the absence of TGFb (Figure1.). The iTreg ratio (CD25+Foxp3+ cells/total CD4+ T cells) was 79.3 ± 17.4% in the culture with IL2/TGFb/Eve, 53.1 ± 23.8% with IL2/TGFb, 35.5±18.6% with IL2/Eve and 22.7 ± 18.6% with IL2, respectively. There was no significant relationship between the dose of Eve and the iTreg ratio, but the highest ratio and induction rate of iTregs were observed at 10nM Eve. Thus, an average of 2.95 ± 2.8 ×107 iTregs was obtained from 5 ×104 CB-CD4+ T cells after two weeks of culture with IL2/TGFb/Eve. The iTreg-rich population cultured with IL2/TGFb/Eve and IL2/TGFb, but not IL2 alone, efficiently inhibited MLR triggered by allogeneic DCs (Figure 2.). These iTregs were also active in MLR using allogeneic responder T cells. Interestingly, IL2/Eve-treated CB-CD4+ T cells also inhibited MLR, irrespective of the low or moderate iTreg ratio. The inhibitory effect on MLR was much less observed by another mTOR inhibitor, rapamycin, rather than Eve (Figure2). Expression of CD26 on CD4+ T cells was inversely correlated to Foxp3 expression and significantly down-regulated by TGFb with or without Eve. Discussion: Treatment of CB-CD4+ T cells with IL2/TGFb/Eve results in the efficient ex vivo expansion of functional iTregs. Eve enhanced TGFb induction of Foxp3 expression, but did not induce Foxp3 expression by itself. mTOR is a complex of TORC1 and 2. Rapamycin is reported to inhibit TORC1, while Eve inhibits both of them, at general dose. In recent report, mTOR-deficient T cells (TORC1/2, not TORC1 alone) displayed normal activation and IL-2 production upon initial stimulation, but failed to differentiate into effecter T cells, instead, differentiated into Tregs. Although the direct mechanism to inhibit MLR by CB-CD4+ T cells treated with Eve remained to be elucidated, these results suggested the aberrant pathways of immunological inhibition. Disclosures: No relevant conflicts of interest to declare.

Role of regulatory T-cells in autoimmunity

2009 ◽  
Vol 116 (8) ◽  
pp. 639-649 ◽  
Author(s):  
Richard J. Mellanby ◽  
David C. Thomas ◽  
Jonathan Lamb
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Treg Cell ◽  
Cell Function ◽  
Cell Subset ◽  
Treg Cells ◽  
Self Tolerance

There has been considerable historical interest in the concept of a specialist T-cell subset which suppresses over-zealous or inappropriate T-cell responses. However, it was not until the discovery that CD4+CD25+ T-cells had suppressive capabilities both in vitro and in vivo that this concept regained credibility and developed into one of the most active research areas in immunology today. The notion that in healthy individuals there is a subset of Treg-cells (regulatory T-cells) involved in ‘policing’ the immune system has led to the intensive exploration of the role of this subset in disease resulting in a number of studies concluding that a quantitative or qualitative decline in Treg-cells is an important part of the breakdown in self-tolerance leading to the development of autoimmune diseases. Although Treg-cells have subsequently been widely postulated to represent a potential immunotherapy option for patients with autoimmune disease, several studies of autoimmune disorders have demonstrated high numbers of Treg-cells in inflamed tissue. The present review highlights the need to consider a range of other factors which may be impairing Treg-cell function when considering the mechanisms involved in the breakdown of self-tolerance rather than focussing on intrinsic Treg-cell factors.

Loss of FOXP3 Expression and Emergence of Cytokine-Producing Cells after In Vitro Expansion of Human CD4+CD25+CD127 - Regulatory T Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 63-63 ◽  
Author(s):  
Petra Hoffmann ◽  
Ruediger Eder ◽  
Tina J. Boeld ◽  
Jochen Huehn ◽  
Stefan Floess ◽  
...  
Keyword(s):  
T Cells ◽  
Treg Cell ◽  
Cell Cultures ◽  
Methylation Status ◽  
Foxp3 Expression ◽  
Treg Cells ◽  
Culture Conditions ◽  
Cell Therapies ◽  
Over Time

Abstract We and others previously showed that the adoptive transfer of donor-type CD4+CD25+ regulatory T (Treg) cells protects from graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (SCT) in animal models. Exploring this strategy in human SCT, we currently perform a first Phase I clinical trial using freshly isolated Treg cells. For future trials requiring large Treg cell numbers for repetitive treatments, we described in vitro culture conditions that permit a more than 3-log expansion of polyclonal Treg cells (Blood 104:895; 2004). A highly enriched starting population proved to be crucial for the generation of pure Treg cell products and we could show that the naive, CD45RA+ subpopulation of CD4+CD25high T cells fulfills this criterion (Blood108:4260; 2006). A recently proposed alternative approach for the isolation of pure Treg cells relies on the exclusion of CD127+ cells, as activated (i.e. CD25+) conventional T cells express high levels of CD127 while CD4+CD25+ Treg cells show no or only weak expression levels (Seddiki et al. and Liu et al., JEM203:1693; 2006). To directly compare these two approaches, we isolated CD4+CD25+CD127low/neg T cells (CD127-Treg) and CD45RA+CD4+CD25high T cells (RA+ Treg) from the same leukapheresis products and analyzed the cells after 2 and 3 weeks of expansion. Whereas both populations were > 94% FOXP3+ upon isolation, only RA+ Treg maintained this high level of FOXP3+ cells throughout the expansion period (93% (range: 78 to 97%; n=11) FOXP3+ after 2 and 87% (range: 71 to 97%; n=9) FOXP3+ after 3 weeks). In contrast, the proportion of FOXP3+ cells in CD127-Treg cultures was already reduced after 2 weeks (82% (range: 56 to 96%; n=11)) and highly variable and significantly lower than that of RA+ Treg cultures after 3 weeks (57% (range: 18 to 93%; n=9; p=0.006)). When further subdivided into CD45RA+ and CD45RA- subpopulations before expansion, cultures of CD45RA-CD127-Treg cells lost FOXP3 expression and comprised substantial numbers of FOXP3- cytokine producing cells (on average 54% and 38% IL-2 and IFN-γ producers, respectively) after 3 weeks, whereas CD45RA+ CD127- Treg behaved similar to RA+ Treg cells, as they maintained FOXP3 expression over time and contained only low numbers of cytokine producers. Furthermore, when we analyzed the DNA methylation status of Treg cells, we found the Treg-specific CpG demethylation pattern within the FOXP3 gene (EJI 37, 2007) in RA+ Treg cell lines, while CD127- Treg cell cultures showed increased methylation over time and even more so RA- Treg cell cultures. Based on these findings, we suggest that isolation and expansion of CD45RA+CD4+CD25high T cells at present represents the best strategy for adoptive cell therapies requiring in vitro expanded Treg cells.

scholarly journals Secretome screening reveals immunomodulating functions of IFNα-7, PAP and GDF-7 on regulatory T-cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mei Ding ◽  
Rajneesh Malhotra ◽  
Tomas Ottosson ◽  
Magnus Lundqvist ◽  
Aman Mebrahtu ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Cell Function ◽  
Foxp3 Expression ◽  
Treg Cells ◽  
Secreted Proteins ◽  
External Stimulation ◽  
Marker Proteins ◽  
Positive Regulators ◽  
Conformational Model

AbstractRegulatory T cells (Tregs) are the key cells regulating peripheral autoreactive T lymphocytes. Tregs exert their function by suppressing effector T cells. Tregs have been shown to play essential roles in the control of a variety of physiological and pathological immune responses. However, Tregs are unstable and can lose the expression of FOXP3 and suppressive functions as a consequence of outer stimuli. Available literature suggests that secreted proteins regulate Treg functional states, such as differentiation, proliferation and suppressive function. Identification of secreted proteins that affect Treg cell function are highly interesting for both therapeutic and diagnostic purposes in either hyperactive or immunosuppressed populations. Here, we report a phenotypic screening of a human secretome library in human Treg cells utilising a high throughput flow cytometry technology. Screening a library of 575 secreted proteins allowed us to identify proteins stabilising or destabilising the Treg phenotype as suggested by changes in expression of Treg marker proteins FOXP3 and/or CTLA4. Four proteins including GDF-7, IL-10, PAP and IFNα-7 were identified as positive regulators that increased FOXP3 and/or CTLA4 expression. PAP is a phosphatase. A catalytic-dead version of the protein did not induce an increase in FOXP3 expression. Ten interferon proteins were identified as negative regulators that reduced the expression of both CTLA4 and FOXP3, without affecting cell viability. A transcriptomics analysis supported the differential effect on Tregs of IFNα-7 versus other IFNα proteins, indicating differences in JAK/STAT signaling. A conformational model experiment confirmed a tenfold reduction in IFNAR-mediated ISG transcription for IFNα-7 compared to IFNα-10. This further strengthened the theory of a shift in downstream messaging upon external stimulation. As a summary, we have identified four positive regulators of FOXP3 and/or CTLA4 expression. Further exploration of these Treg modulators and their method of action has the potential to aid the discovery of novel therapies for both autoimmune and infectious diseases as well as for cancer.

scholarly journals Trichostatin A Promotes the Generation and Suppressive Functions of Regulatory T Cells

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Cristian Doñas ◽  
Macarena Fritz ◽  
Valeria Manríquez ◽  
Gabriela Tejón ◽  
María Rosa Bono ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Trichostatin A ◽  
Gene Promoter ◽  
Treg Cells ◽  
Specific Subset ◽  
Global Increase ◽  
And Function ◽  
H3 Acetylation

Regulatory T cells are a specific subset of lymphocytes that suppress immune responses and play a crucial role in the maintenance of self-tolerance. They can be generated in the thymus as well as in the periphery through differentiation of naïve CD4+T cells. The forkhead box P3 transcription factor (Foxp3) is a crucial molecule regulating the generation and function of Tregs. Here we show that thefoxp3gene promoter becomes hyperacetylated inin vitrodifferentiated Tregs compared to naïve CD4+T cells. We also show that the histone deacetylase inhibitor TSA stimulated thein vitrodifferentiation of naïve CD4+T cells into Tregs and that this induction was accompanied by a global increase in histone H3 acetylation. Importantly, we also demonstrated that Tregs generated in the presence of TSA have phenotypical and functional differences from the Tregs generated in the absence of TSA. Thus, TSA-generated Tregs showed increased suppressive activities, which could potentially be explained by a mechanism involving the ectonucleotidases CD39 and CD73. Our data show that TSA could potentially be used to enhance the differentiation and suppressive function of CD4+Foxp3+Treg cells.

scholarly journals CD38 Correlates with an Immunosuppressive Treg Phenotype in Lupus-Prone Mice

2021 ◽  
Vol 22 (21) ◽  
pp. 11977
Author(s):  
Jocelyn C. Pérez-Lara ◽  
Enrique Espinosa ◽  
Leopoldo Santos-Argumedo ◽  
Héctor Romero-Ramírez ◽  
Gabriela López-Herrera ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Immune Activation ◽  
Lupus Erythematosus ◽  
Clinical Signs ◽  
Foxp3 Expression ◽  
Cell Receptor ◽  
Treg Cells ◽  
Transmembrane Glycoprotein ◽  
Ifn Γ

CD38 is a transmembrane glycoprotein expressed by T-cells. It has been reported that patients with systemic lupus erythematosus (SLE) showed increased CD38+CD25+ T-cells correlating with immune activation and clinical signs. Contrariwise, CD38 deficiency in murine models has shown enhanced autoimmunity development. Recent studies have suggested that CD38+ regulatory T-cells are more suppressive than CD38− regulatory T-cells. Thus, we have suggested that CD38 overexpression in SLE patients could play a role in regulating immune activation cells instead of enhancing it. This study found a correlation between CD38 with FoxP3 expression and immunosuppressive molecules (CD69, IL-10, CTLA-4, and PD-1) in T-cells from lupus-prone mice (B6.MRL-Faslpr/J). Additionally, B6.MRL-Faslpr/J mice showed a decreased proportion of CD38+ Treg cells regarding wild-type mice (WT). Furthermore, Regulatory T-Cells (Treg cells) from CD38-/- mice showed impairment in expressing immunosuppressive molecules and proliferation after stimulation through the T-cell receptor (TCR). Finally, we demonstrated an increased ratio of IFN-γ/IL-10 secretion in CD38-/- splenocytes stimulated with anti-CD3 compared with the WT. Altogether, our data suggest that CD38 represents an element in maintaining activated and proliferative Treg cells. Consequently, CD38 could have a crucial role in immune tolerance, preventing SLE development through Treg cells.

scholarly journals Comparing the Effects of the mTOR Inhibitors Azithromycin and Rapamycin on In Vitro Expanded Regulatory T Cells

2019 ◽  
Vol 28 (12) ◽  
pp. 1603-1613 ◽  
Author(s):  
Marcus Bergström ◽  
Malin Müller ◽  
Marie Karlsson ◽  
Hanne Scholz ◽  
Nils Tore Vethe ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Ex Vivo ◽  
Mtor Inhibitors ◽  
Allogeneic Transplantation ◽  
Suppressive Effect ◽  
And Function ◽  
Treg Phenotype ◽  
Suppression Assay

Adoptive transfer of autologous polyclonal regulatory T cells (Tregs) is a promising option for reducing graft rejection in allogeneic transplantation. To gain therapeutic levels of Tregs there is a need to expand obtained cells ex vivo, usually in the presence of the mTOR inhibitor Rapamycin due to its ability to suppress proliferation of non-Treg T cells, thus promoting a purer Treg yield. Azithromycin is a bacteriostatic macrolide with mTOR inhibitory activity that has been shown to exert immunomodulatory effects on several types of immune cells. In this study we investigated the effects of Azithromycin, compared with Rapamycin, on Treg phenotype, growth, and function when expanding bulk, naïve, and memory Tregs. Furthermore, the intracellular concentration of Rapamycin in CD4+ T cells as well as in the culture medium was measured for up to 48 h after supplemented. Treg phenotype was assessed by flow cytometry and Treg function was measured as inhibition of responder T-cell expansion in a suppression assay. The concentration of Rapamycin was quantified with liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). Azithromycin and Rapamycin both promoted a FoxP3-positive Treg phenotype in bulk Tregs, while Rapamycin also increased FoxP3 and FoxP3+Helios positivity in naïve and memory Tregs. Furthermore, Rapamycin inhibited the expansion of naïve Tregs, but also increased their suppressive effect. Rapamycin was quickly degraded in 37°C medium, yet was retained intracellularly. While both compounds may benefit expansion of FoxP3+ Tregs in vitro, further studies elucidating the effects of Azithromycin treatment on Tregs are needed to determine its potential use.

scholarly journals Context-Dependent Effect of Glucocorticoids on the Proliferation, Differentiation, and Apoptosis of Regulatory T Cells: A Review of the Empirical Evidence and Clinical Applications

2019 ◽  
Vol 20 (5) ◽  
pp. 1142 ◽  
Author(s):  
Luigi Cari ◽  
Francesca De Rosa ◽  
Giuseppe Nocentini ◽  
Carlo Riccardi
Keyword(s):  
T Cells ◽  
Treg Cell ◽  
Inflammatory Diseases ◽  
Treg Cells ◽  
Cell Number ◽  
Lymphoid Tissues ◽  
Treg Number ◽  
Context Dependent

Glucocorticoids (GCs) are widely used to treat several diseases because of their powerful anti-inflammatory and immunomodulatory effects on immune cells and non-lymphoid tissues. The effects of GCs on T cells are the most relevant in this regard. In this review, we analyze how GCs modulate the survival, maturation, and differentiation of regulatory T (Treg) cell subsets into both murine models and humans. In this way, GCs change the Treg cell number with an impact on the mid-term and long-term efficacy of GC treatment. In vitro studies suggest that the GC-dependent expansion of Treg cells is relevant when they are activated. In agreement with this observation, the GC treatment of patients with established autoimmune, allergic, or (auto)inflammatory diseases causes an expansion of Treg cells. An exception to this appears to be the local GC treatment of psoriatic lesions. Moreover, the effects on Treg number in patients with multiple sclerosis are uncertain. The effects of GCs on Treg cell number in healthy/diseased subjects treated with or exposed to allergens/antigens appear to be context-dependent. Considering the relevance of this effect in the maturation of the immune system (tolerogenic response to antigens), the success of vaccination (including desensitization), and the tolerance to xenografts, the findings must be considered when planning GC treatment.

Sign in / Sign up

Export Citation Format

Share Document