State Of Immune Tolerance Research Articles

Pyoderma Gangrenosum Following Cesarean Delivery

We describe the case of a 30-year-old woman who, 5 days after giving birth to her first child by cesarean section, presented with dehiscence of one end of the surgical wound and a lesion on her leg that developed into a well-defined ulcer; both lesions were very painful. The patient was initially diagnosed with a skin infection and later with superficial pyoderma gangrenosum. The lesions were treated with topical corticosteroids and a good response was observed. No evidence was found of underlying disease. Isolated cases of pyoderma gangrenosum associated with pregnancy or cesarean delivery have been reported in the literature. The etiology of pyoderma gangrenosum is currently unknown, but some theories suggest an immunologic mechanism. Gestation is known to generate a state of immune tolerance that could play a role in the development of the disease and future studies may help to clarify the significance of this association.

Hematopoiesis from Human Embryonic Stem Cells: Overcoming the Immune Barrier in Stem Cell Therapies

The multipotency and proliferative capacity of human embryonic stem cells (hESCs) make them a promising source of stem cells for transplant therapies and of vital importance given the shortage in organ donation. Recent studies suggest some immune privilege associated with hESC-derived tissues. However, the adaptability of the immune system makes it unlikely that fully differentiated tissues will permanently evade immune rejection. One promising solution is to induce a state of immune tolerance to a hESC line using tolerogenic hematopoietic cells derived from it. This could provide acceptance of other differentiated tissues from the same line. However, this approach will require efficient multilineage hematopoiesis from hESCs. This review proposes that more efficient differentiation of hESCs to the tolerogenic cell types required is most likely to occur through applying knowledge gained of the ontogeny of complex regulatory signals used by the embryo for definitive hematopoietic development in vivo. Stepwise formation of mesoderm, induction of definitive hematopoietic stem cells, and the application of factors key to their self-renewal may improve in vitro production both quantitatively and qualitatively.

Therapeutic Potential of CD4+ CD25+ Regulatory T Cells in Allogeneic Transplantation

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Diminished Expression and Function of TLR in Lymphatic Filariasis: A Novel Mechanism of Immune Dysregulation

Lymphatic filariasis is a disease characterized by immune dysregulation involving APC and T cell populations. To assess the contribution of TLR in mediating this dysregulation, we examined the expression of TLR1, TLR2, TLR4, and TLR9 on B cells and monocytes of filaria-infected and uninfected individuals. Baseline expression of TLR was significantly lower in B cells but not in monocytes of the filaria-infected group compared with the uninfected group. Upon stimulation with filarial Ag, a diminished up-regulation of TLR was observed in both B cells and monocytes of infected individuals. Finally, stimulation of B cells and monocytes with TLR ligands resulted in decreased B cell and monocyte activation/cytokine production, indicating a state of immune tolerance. This dysregulation is associated with diminished CD4(+) T cell production of IFN-gamma and IL-5. The diminished expression and function of TLR is thus a likely consequence of chronic Ag stimulation and could serve as a novel mechanism underlying the dysfunctional immune response in filariasis.

Therapeutic potential of CD4+ CD25+ regulatory T cells in allogeneic transplantation

The subpopulation of CD4+ CD25+ immunoregulatory T cells constitutes less than of the entire CD4+ T-cell pool in mice and 2% in humans. These cells play a crucial role in the control of autoimmune processes. More recently, in vitro and in vivo data also indicate that CD4+ CD25+ immunoregulatory T cells can regulate alloreactivity. This renders them good candidates for innovative strategies in the field of transplantation. Inducing a state of immune tolerance with immunoregulatory T cells would alleviate the need for immunosuppression, and the occurrence of late allograft failure represents a major goal of transplantation immunology. Here we discuss how these naturally occurring CD4+ CD25+ immunoregulatory T cells can be used to modulate alloreactivity in hematopoietic stem cell and solid organ transplantation.

Pregnancy-induced expansion of regulatory T-lymphocytes may mediate protection to multiple sclerosis activity

Pregnancy represents a physiological transitory state of immune tolerance to avoid the rejection of the foetus, and concomitantly of stabilisation of many autoimmune diseases, such as multiple sclerosis (MS). Alterations in regulatory T-lymphocytes (T Reg) are known to be involved in organ-specific autoimmune disease pathophysiology. Our goal was to quantify CD4 +CD25 + and CD4 +CD25 hi+ T Reg and activated (CD4 +HLA-DR +CD38 +) T-lymphocytes during pregnancy and puerperium in 13 MS patients in comparison with healthy pregnant and non-pregnant women. During pregnancy, a progressive parallel increase in CD4 +CD25 + T-lymphocytes in healthy pregnants as well as MS pregnant patients was observed. The proportion of T Reg was significantly higher in all pregnants than in non-pregnant women ( p = 0.01), whereas no differences were observed neither in the percentages of total nor activated CD4 + T-lymphocytes. In MS patients, CD4 +CD25 + T-lymphocytes significantly decreased when comparing the third trimester with the puerperal period proportions ( p = 0.01), whereas CD4 +CD25 hi+ T-lymphocytes significantly increased ( p = 0.002). Our findings are consistent with the expansion of circulating regulatory CD4 +CD25 + T-lymphocytes pool with suppressive activity during normal pregnancy and in MS. A different pattern of CD4 +CD25 hi+ T-lymphocytes between healthy pregnants and MS women, which may represent relevant factors in the activity course of MS.

Antibody-induced transplantation tolerance: the role of dominant regulation.

A short-treatment with nondepleting antibodies, such as those targeting CD4 or CD154 (CD40 ligand), allows long-term graft survival without the need for continuous immunosuppression. This state of immune tolerance is maintained by regulatory CD4+ T cells present within both the lymphoid tissue and the tolerated graft. The nature of such regulatory T cells, their relationship to CD4+CD25+ T cells, and their mode of action have all been the subjects of much attention recently. Here, we review recent progress on understanding the nature, specificity, and mechanisms of action of T cells mediating dominant tolerance brought about by antibody therapy.

Improvement of autoimmune hepatitis during pregnancy followed by flare-up after delivery.

Pregnancy in autoimmune hepatitis has been a rare event, but it has become more frequent with improved therapy. The present study aimed to analyze the consequences for mother and child in patients with autoimmune hepatitis. Fourteen pregnancies have been followed in five patients with autoimmune chronic hepatitis (AIH) and in one with autoimmune sclerosing cholangitis (overlap AIH-PSC). Features of AIH improved markedly from the second trimester of pregnancy onward, allowing a decrease in immunosuppressive therapy. After delivery (or stillbirth in one patient), the activity of the autoimmune disease flared up rapidly in 12 of 14 events. Pregnancy induces a state of immune tolerance with improvement of the liver tests in AIH. This could result from a transition of TH1 to TH2 predominance during pregnancy. A flare-up often occurs after delivery. Preemptive increase of the immunosuppressive therapy is therefore advocated consecutive to delivery. Azathioprine use seems to be safe during pregnancy.

Improvement of autoimmune hepatitis during pregnancy followed by flare-up after delivery

OBJECTIVES: Pregnancy in autoimmune hepatitis has been a rare event, but it has become more frequent with improved therapy. The present study aimed to analyze the consequences for mother and child in patients with autoimmune hepatitis. METHODS: Fourteen pregnancies have been followed in five patients with autoimmune chronic hepatitis (AIH) and in one with autoimmune sclerosing cholangitis (overlap AIH-PSC). RESULTS: Features of AIH improved markedly from the second trimester of pregnancy onward, allowing a decrease in immunosuppressive therapy. After delivery (or stillbirth in one patient), the activity of the autoimmune disease flared up rapidly in 12 of 14 events. CONCLUSIONS: Pregnancy induces a state of immune tolerance with improvement of the liver tests in AIH. This could result from a transition of T H1 to T H2 predominance during pregnancy. A flare-up often occurs after delivery. Preemptive increase of the immunosuppressive therapy is therefore advocated consecutive to delivery. Azathioprine use seems to be safe during pregnancy.

OX40 ligation enhances primary and memory cytotoxic T lymphocyte responses in an immunotherapy for hepatic colon metastases.

Previously, we showed that the eradication of murine hepatic metastatic colon carcinomas was achieved by using a combination therapy with adenovirus-mediated gene delivery of interleukin 12 (IL-12) and anti-4-1BB agonistic antibody. However, the therapeutic efficacy was compromised severely when mice with tumors larger than 8 x 8 mm(2) were treated. In this report, we studied the effect of OX40 costimulation through agonistic anti-OX40 in combination with the IL-12 + anti-4-1BB immunotherapy on primary and memory anti-tumor cytotoxic T lymphocyte responses in a large-tumor setting (8 x 8 to 12 x 12 mm(2)). Tumor-infiltrating leukocytes (TILs) isolated from mice treated with the combination therapy of IL-12, anti-4-1BB, and anti-OX40 showed a significantly higher ex vivo direct cytotoxic T lymphocyte (CTL) activity against parental tumors, as compared with those from mice treated with IL-12 and anti-4-1BB. In vivo depletion of CD4(+)T cells during combination therapy significantly decreased the number of tumor-infiltrating CD8(+)T cells and their cytotoxic activity in mice treated with IL-12 + anti-4-1BB + anti-OX40 combination therapy but not in the group treated with IL-12 + anti-4-1BB, which indicated that in vivo OX40 engagement on CD4(+) T cells led to the higher CTL responses observed in animals treated with IL-12 + anti-4-BB + anti-OX40 combination therapy. Furthermore, the combination therapy of IL-12, anti-4-1BB, and anti-OX40 resulted in a significantly higher survival rate in treated mice, as compared with treatment with IL-12 and anti-4-1BB. More importantly, long-term surviving mice from the combination therapy with IL-12, anti-4-1BB, and anti-OX40 exhibited higher memory CTL responses against parental tumor cells. The results demonstrated that OX40 ligation of CD4(+) T cells facilitated the development of primary and memory CTL responses against tumorcells and that coordinated immune activation by IL-12, anti-4-1BB, and anti-OX40 resulted in a significantly higher survival rate in mice with large tumor burdens. Thus, the combination therapy with the adenovirus encoding IL-12 (Adv.mIL-12) + anti-4-1BB + anti-OX40 antibodies may provide a better treatment modality for patients with advanced cancers, often associated with a state of immune suppression or tolerance.

DCs Show Self-Control

Dendritic cells (DCs) are increasingly being recognized for their ability to shut down some types of immune response and for contributing to the state of immune tolerance. Elucidation of putative tolerogenic DC subsets is underway, although the mechanisms by which these cells might modulate immunity have yet to be established. Munn et al. now describe a subset of human DCs that can inhibit T cell responses, at least in vitro, to alloantigens through the catabolism of tryptophan by the enzyme indoleamine 2,3-dioxygenase (IDO). It is known that IDO can prevent antigen-specific responses of T cells in vivo as well as in vitro. The present demonstration that a subset of human DCs can inhibit T cell responses via IDO in vitro makes it plausible that these cells might use the same mechanism in vivo. Whether DCs actually regulate immune responses to self-antigens, transplants, and tumors by this mechanism remains to be established. D. H. Munn, M. D. Sharma, J. R. Lee, K. G. Jhaver, T. S. Johnson, D. B. Keskin, B. Marshall, P. Chandler, S. J. Antonia, R. Burgess, C. L. Slingluff Jr., A. L. Mellor, Potential regulatory function of human dendritic cells expressing indoleamine 2,3-dioxygenase. Science 297 , 1867-1870 (2002). [Abstract] [Full Text]

A view on beta cell transplantation in diabetes.

Organ donors also offer a source of insulin-producing tissue that might be used for the treatment of diabetes. Clinical protocols for transplantation of this tissue aim for the prevention of chronic diabetes complications without introducing new serious side effects. Pancreas and islet cell transplantation are discussed in this perspective. The future of islet cell implants looks favorable but depends on finding ways to induce immune tolerance to the donor beta cells. Clinical trials can take advantage of relevant progress in animal models. In a limited study, recipient treatment with antilymphocyte antibodies and culture of donor cell preparations appeared useful to induce a state of operational immune tolerance in type 1 diabetic patients, as indirectly judged by graft survival and by analysis of auto- and alloreactivities in recipients. Use of cultured beta cell preparations also allows donor cell recruitment from suboptimal donor organs and increases the degree of standardization and quality control of islet cell grafts. The future of these grafts will depend on the development of techniques for the neogenesis of beta cells.

Transplantation of developing kidneys

The number of kidney transplantations performed per year is limited by the availability of donor organs. One novel solution to this shortage envisions growing new kidneys in situ through xenotransplantation of renal anlagen. To be successful, such an approach will require that: (1) transplants are grown in a location that renders possible their subsequent excretory function, (2) developed transplants have normal morphological characteristics and function, (3) transplanted metanephroi become well integrated into the host in terms of inducing a state of immune tolerance and being vascularized by host vessels, and (4) source material for metanephros transplants is readily available. This review summarizes experimental data relating to these requirements for the transplantation of developing kidneys.

Recommendations of the National Heart, Lung and Blood Institute Heart and Lung Tolerance Working Group.

Recommendations of the National Heart, Lung and Blood Institute Heart and Lung Tolerance Working Group.

Postpartum thyroiditis and autoimmune thyroiditis in women of childbearing age: recent insights and consequences for antenatal and postnatal care.

Postpartum thyroiditis is a syndrome of transient or permanent thyroid dysfunction occurring in the first year after delivery and based on an autoimmune inflammation of the thyroid. The prevalence ranges from 5-7%. We discuss the role of antibodies (especially thyroid peroxidase antibodies), complement, activated T cells, and apoptosis in the outbreak of postpartum thyroiditis. Postpartum thyroiditis is conceptualized as an acute phase of autoimmune thyroid destruction in the context of an existing and ongoing process of thyroid autosensitization. From pregnancy an enhanced state of immune tolerance ensues. A rebound reaction to this pregnancy-associated immune suppression after delivery explains the aggravation of autoimmune syndromes in the puerperal period, e.g., the occurrence of clinically overt postpartum thyroiditis. Low thyroid reserve due to autoimmune thyroiditis is increasingly recognized as a serious health problem. 1) Thyroid autoimmunity increases the probability of spontaneous fetal loss. 2) Thyroid failure due to autoimmune thyroiditis-often mild and subclinical-can lead to permanent and significant impairment in neuropsychological performance of the offspring. 3) Evidence is emerging that as women age subclinical hypothyroidism-as a sequel of postpartum thyroiditis-predisposes them to cardiovascular disease. Hence, postpartum thyroiditis is no longer considered a mild and transient disorder. Screening is considered.

IL-6 and GM-CSF in tumor rejection model of renal cell cancer.

Tumors developing within a host induce a state of immune tolerance to tumor antigens. Number of concepts are tested in order to activate the antitumoral immune response to recognize and destroy tumor cells. Tumor vaccines genetically modified with cytokine genes (GMTV) are one of strategies currently examined. Different cytokines display different patterns of antitumoral immune response activation but the perfect cytokine or a combination of cytokine are still to be found. Here we present two GMTVs one consisting of cells producing IL-6 and the second producing GM-CSF in a murine tumor rejection model of Renal Cell Carcinoma (RenCa).

Cis-Urocanic Acid Induces Mast Cell Degranulation and Release of Preformed TNF--α: A Possible Mechanism Linking UVB and cis-Urocanic Acid to Immunosuppression of Contact Hypersensitivity

The search for effective inhibitors of transdermal drug-induced contact sensitization was directed to dermal mast-cell-degranulating agents (MCDA). Human skin organ cultures were employed to test whether cis-urocanic acid (C-UA) and other potential MCDAs cause mast cell degranulation. These were then tested for their ability to inhibit the induction phase of the contact hypersensitivity reaction (CHR). C-UA at 1 μg/ml significantly depleted mast cell chymase, whereas trans-urocanic acid (T-UA) was relatively ineffective. C-UA, but not T-UA, induced local effects of liberated mast cell TNF-α, as detected by E-selectin expression on the microvascular dermal endothelium. C-UA significantly reduced (>70%) the ear swelling response in Balb/c mice, when applied 24 h prior to application of a sensitizing amount of dinitrochlorobenzene (DNCB), and induced a prolonged (>3 weeks) state of immune tolerance (>40%). Similar effects on local immunosuppression of CHR were observed with topical chloroquine and capsaicin, while cromolyn, a mast cell membrane stabilizer, was unable to inhibit DNCB-induced CHR. It is suggested that MCDAs may interfere with downstream events associated with accessory cell function.

INFLUENCE OF ADDITIONAL ADMINISTRATION OF HOST-TYPE BONE MARROW ON THE IMMUNE TOLERANCE OF MIXED ALLOGENEIC CHIMERAS

640 Tolerance after allogeneic bone marrow transplantation is maintained by clonal deletion, clonal anergy and/or suppressor mechanism. In the present work we examined the state of chimerism and immune tolerance of C3H mice conditionned with TBI followed by injection of T cell depleted (TCD) AKR bone marrow (BM) alone or in combination with TCD syngeneic (C3H) BM. METHODS: Recipient C3H (H-2k, Thy1.2, Mls 2a) mice received 9,5 Gy of TBI and one day after irradiation they were reconstitued with TCD (using Thy1.1 mab and complement) AKR (H-2k, Thy1.1, Mls 1a) bone marrow cells(5×106) alone (group 1) or combined with TCD (using Thy1.2 mab and complement) C3H bone marrow cells (5×106) (group 2). Chimerism was determined at various time points by FACS, using Thy1.2 and Thy1.1 mabs. The percentage of CD4+VB6+ T cells and CD4+VB3+ T cells was also determined by FACS. In order to break tolerance, 40×106 host-type spleenocytes were injected (IV) 2 months after bone marrow transplantation(BMT). RESULTS: Both groups of chimeras showed 100% survival without any clinical or histological signs of GVHD. When assayed between 2 weeks and 3months after BM transplantation, the majority of T cells in the thymus and in the periphery (spleen) of group 1 chimeras were from donor-origin (Thy1.1)(90-95%). In contrast in the group2 chimeras donor T cells represented only between 36-60% off all thymocytes or peripheral T cells. In both group of chimeras, donor-reactive T cells (CD4+VB6+) that recognise Mls 1a antigen in AKR donor were completely deleted in both the thymus and the perifery. In contrast, host-reactive T cells (CD4+VB3+) escaped from deletion early (2 weeks) after BMT in the thymus of group 1 and persisted also in the PBL (3%) whereas they were immediately and totaly deleted in the thymus and continously absent in the perifery of group 2 chimeras. Chimerism was easily broken in group 2 chimeras by injection of host type spleen cells but not in group 1 where it was even followed by an expansion of host-reactive T cells. CONCLUSION: Addition of TCD host-type BM cells to a minor mismatched allogeneic BM inoculum results in: 1) lower degree of donor chimerism, 2) a complete and immediate clonal deletion of host-reactive T cells in the thymus and the perifery, 3) a decresed resistance of the mixed chimeras against breaking of tolerance. It is presently examined whether persistent host-reactive T cells in group 1 chimeras play a role in the resistance against breaking of tolerance.

Autoimmunity Following Neonatal Tolerance to Alloantigens: Role of Donor I-A and I-E Molecules

The injection of semi-allogeneic F1 spleen cells into newborn mice of a parental strain induces a state of immune tolerance characterized by anti-donor CTL unresponsiveness and the appearance of a transient SLE-like autoimmune syndrome associating autoantibody production, hypergammaglobulinemia, splenomegaly and glomerulonephritis. Our previous experiments have demonstrated that host Th2-like CD4+ T lymphocytes activate donor F1 B cells persisting in the host to produce autoantibodies, and that this cellular interaction relies on the presence of alloMHC class II molecules on donor B cells. In order to investigate the role and the involvement of MHC alloantigens in the cellular T(host)-B(donor) interaction, newborn C57BL/6 (B6) mice were injected with F1 spleen cells differing from the host at the level of defined portions of the MHC class I (K) or class II (I-A and I-E) molecules. B6 mice injected at birth with spleen cells from different F1 strains were tolerant to each alloantigen (alloAg) tested, as assessed by specific anti-donor CTL unresponsiveness. However, the SLE-like autoimmune syndrome only developed in B6 mice injected at birth with F1 spleen cells differing at the level of MHC class II I-A or I-E molecules. Autoantibodies appeared later in B6 mice neonatally tolerized to I-E alloAg than those detected in B6 mice neonatally tolerized to I-A alloAg. These results show that the SLE-like autoimmune disease that develops concomitantly to neonatally-induced tolerance to alloAg is the consequence of cognate T host-B donor cellular interactions triggered by even minute differences in the MHC class II I-A or MHC class II I-E molecules.

Gestational diabetes mellitus: evidence for autoimmunity against the pancreatic Beta cells

Diabetes mellitus is a frequent transient or rare permanent complication of pregnancy. The role of autoimmune phenomena in this gestational form of diabetes is incompletely understood. We have examined sera from 312 pregnant women who had abnormal glucose tolerance (based on a screening examination during the second trimester) for the presence of islet cell surface antibodies or insulin autoantibodies. Fifty-eight of these women were lost to follow-up. Of the remaining subjects, 144 (57.1%) had gestational diabetes diagnosed by formal glucose tolerance testing and the others (42.9%) were normal. Sixty percent of the women with gestational diabetes eventually required insulin to control their blood glucose during pregnancy. One serum from the non-diabetic women was positive for insulin antibodies (0.9%); 8 of the sera from the patients with gestational diabetes were positive (5.6%). Subsequent analysis revealed that all nine of the women whose sera were positive for insulin autoantibodies had been treated with insulin previously. Islet cell surface antibodies were strongly correlated with gestational diabetes. Forty-five of 144 gestational diabetic sera were positive (31.3%) whereas only 9 of 108 suspect control sera (8.3%) and 7 of 60 unknown sera (11.7%) were positive. These data suggest that a high percentage of pregnant women who screen positive for glucose intolerance have serological evidence of an autoimmune response against the pancreatic islets, in spite of the state of relative immune tolerance during pregnancy. These data suggest that autoimmune phenomena may play a role in gestational diabetes and that the presence of islet cell antibodies can predict insulin-requiring gestational diabetes.