scholarly journals The nature and kinetics of a delayed immune response to purified protein derivative of tuberculin in the skin of lepromatous leprosy patients.

1988 ◽  
Vol 168 (5) ◽  
pp. 1811-1824 ◽  
Author(s):  
G Kaplan ◽  
S Laal ◽  
G Sheftel ◽  
A Nusrat ◽  
I Nath ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Light And Electron Microscopy ◽  
Lepromatous Leprosy ◽  
Mononuclear Phagocytes ◽  
Lymphoid Cells ◽  
Maximum Diameter ◽  
Purified Protein Derivative ◽  
Constant Feature ◽  
Kinetics Of

We have analyzed the nature and kinetics of a delayed, cell-mediated immune response to a purified protein derivative of tuberculin (PPD) in the skin of 154 naturally sensitized patients with lepromatous leprosy. After the intradermal injection of 5 U of PPD, biopsies were taken at 1-21 d and studied for the composition, extent, persistence, and organization of the emigratory cell response by light and electron microscopy. Induration of positive sites occurred promptly, reached a maximum diameter at 4 d, displayed a major extravasatory element, and was evident for as long as 21 d. The cellularity of the site exhibited a biphasic course, reached a maximum at 7 d, involved as much as 70% of the dermis and millions of new cells, and was elevated threefold above preinjection levels at 21 d. The emigratory cells were limited to T cells and circulating monocytes. T cells were more evident as they entered a preexisting lepromatous lesion containing parasitized macrophages and only occasional T cells many of the CD8+ phenotype. The predominant emigratory T cell was CD4+ although CD8+ cells were in evidence. The CD4/CD8 ratio of the lesions started at less than unity and in two distinct steps reached levels as high as 5:1. In most sites CD4+ cells were in the majority at 21 d. A well-defined granulomatous response with epithelioid and giant cells was apparent at 4 d, reached a maximum at 7 d, and involved all PPD sites at this time point. The generation of these differentiated mononuclear phagocytes from newly emigrated monocytes was never observed in the underlying lepromatous lesion but is a constant feature of the tuberculoid leprosy response. Epidermal thickening and keratinocyte proliferation, sequellae of the dermal reaction, reached a maximum at 7 d and gradually resolved by 3 wk. A constant feature of the PPD response was the extensive destruction of preexisting macrophages containing Mycobacterium leprae bacilli or their products. This was associated with the presence of and intimate contact with highly polarized lymphoid cells of unknown phenotype. Cell destruction did not involve other elements of the dermis and spared parasitized Schwann cells. Newly emigrated T cells and monocytes were never seen within the perineural sheath in contact with neural elements. It appears that a single antigenic stimulus leads to a very long-term, defined series of events with distinct temporal patterns. It includes waves of emigratory T cells, the maturation and organization of monocytes, the generation of killer cells, and the extensive destruction of parasitized macrophages.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals ALLOANTISERUM-INDUCED INHIBITION OF IMMUNE RESPONSE GENE PRODUCT FUNCTION

1974 ◽  
Vol 139 (3) ◽  
pp. 679-695 ◽  
Author(s):  
Ethan M. Shevach ◽  
Ira Green ◽  
William E. Paul
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Lymphocytes ◽  
Cell Surface ◽  
Glutamic Acid ◽  
Gene Product ◽  
Lymphoid Cells ◽  
Immune Response Gene ◽  
Ga Response ◽  
Ir Genes

It has been previously demonstrated that alloantisera can specifically block the activation of T lymphocytes by antigens, the response to which is linked to the presence of histocompatibility (H) types against which the alloantisera are directed. Thus, strain 13 anti-2 serum can inhibit the activation of (2 x 13)F1 T lymphocytes by a DNP derivative of a copolymer of L-glutamic acid and L-lysine (DNP-GL), an antigen the response to which is controlled by a 2-linked Ir gene. It was proposed that alloantisera can inhibit T-lymphocyte antigen recognition through interference with the activity of immune response (Ir) gene products. In order to further study whether the inhibitory antibodies within the alloantisera are directed against H antigens or against the products of the Ir genes, we have examined whether the anti-2 serum can inhibit the function of an Ir gene (the L-glutamic acid and L-alanine [GA] gene), which is normally linked to strain 2 H genes when this gene occurs in an outbred animal lacking strain 2 H genes. In the majority of cases, the anti-2 serum was capable of inhibiting the in vitro proliferative response to GA of T cells derived from animals that were GA+2+, but the serum had little if any effect on the GA response of T cells from GA+2- animals. Furthermore, an antiserum prepared in strain 13 animals against the lymphoid cells of a GA+2- outbred animal was devoid of inhibitory activity on the GA response of cells from a (2 x 13)F1, while an antiserum prepared in strain 13 animals against the lymphoid cells of a GA+2+ outbred animal was capable of specifically inhibiting the response to GA. It thus appears that the inhibition of the GA response by the anti-2 serum is primarily mediated via antibodies directed toward strain 2 H antigens rather than antibodies specific for the product of the GA Ir gene. The mechanism of alloantiserum induced suppression of Ir gene function would then be by steric interference with the Ir gene product on the cell surface, rather than by direct binding to it. This conclusion implies that the products of both the H genes and the Ir genes are physically related on the cell surface. The implications of such a relationship in terms of the fluid-mosaic model of the lymphocyte surface are discussed.

scholarly journals GENETIC CONTROL OF THE IMMUNE RESPONSE

1972 ◽  
Vol 136 (5) ◽  
pp. 1195-1206 ◽  
Author(s):  
John C. Ordal ◽  
F. Carl Grumet
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Genetic Control ◽  
Antibody Production ◽  
Lymphoid Cells ◽  
Antigen Challenge ◽  
Graft Versus Host ◽  
K Cells

The transfer of parental (H-2k/k) nonresponder lymphoid cells into heterozygous (H-2k/q) nonresponder recipients at the time of primary challenge with aqueous poly-L(Tyr,Glu)-poly-D,L-Ala-poly-L-Lys [(T,G)-A--L] elicited the production of both IgM and IgG anti-(T,G)-A--L antibody. Normally, the production of IgG anti-(T,G)-A--L antibody is restricted to strains possessing the responder Ir-1 allele. The timing and intensity of the graft-versus-host (GVH) reaction required for this effect were found to be critical. Injection of H-2k/k cells into H-2k/q recipients 1 wk before antigen challenge did not elicit IgG anti-(T,G)-A--L antibody production, and markedly suppressed IgM anti-(T,G)-A--L antibody production. The transfer of alloimmune (H-2q-primed) H-2k/k cells at the time of antigen challenge was also associated with no IgG and little IgM anti-(T,G)-A--L antibody production. These data are consistent with the model that nonresponder thymus-derived lymphocytes (T cells) activated in a GVH reaction can substitute for (T,G)-A--L-reactive T cells to induce a shift from IgM to IgG anti-(T,G)-A--L antibody production.

scholarly journals The systemic influence of recombinant interleukin 2 on the manifestations of lepromatous leprosy.

1991 ◽  
Vol 173 (4) ◽  
pp. 993-1006 ◽  
Author(s):  
G Kaplan ◽  
W J Britton ◽  
G E Hancock ◽  
W J Theuvenet ◽  
K A Smith ◽  
...  
Keyword(s):  
T Cells ◽  
Endothelial Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Interleukin 2 ◽  
Body Burden ◽  
Lepromatous Leprosy ◽  
Lymphoid Cells ◽  
Peripheral Blood Mononuclear ◽  
Recombinant Interleukin 2

14 patients with lepromatous leprosy received twice daily injections of 10 micrograms recombinant interleukin 2 (rIL-2), by the intradermal route, in the skin of the back for 8 d (total dose, 160 micrograms). Lymphokine administration was accomplished without drug toxicity, or the development of acute nerve damage. The majority of patients developed nontender axillary lymphadenopathy during the course of treatment. Local injection sites showed progressively larger zones of induration, peaking at 24 h and persisting for many days. Early 12-h reactions were of a macular, erythematous nature and exhibited an increasingly striking diurnal variation. The morning injection sites were three- to fourfold larger in diameter than those placed in the evening (9 am to 9 pm). Systemic manifestations of intradermal rIL-2 administration were noted. Peripheral blood T cells, including CD4+ and CD8+ phenotypes, increased 2-2.5-fold and NK cells increased sixfold. Elevations in [3H]TdR incorporation into peripheral blood mononuclear cells occurred to a variety of mycobacterial antigens, but not to those of Mycobacterium leprae. Within 2 wk, biopsies at sites far removed from the back showed increased infiltration of mononuclear cells in 12 of 14 patients. Immunocytochemistry revealed the presence of newly emigrated CD4+ T cells, monocytes, and dermal CD1+ Langerhans cells. Endothelial cells of small dermal vessels expressed major histocompatibility complex class II determinants on their surface. Transmission electron microscopy of these specimens revealed markedly enlarged endothelial cells with many surface projections extending into the lumen as well as extravasating lymphoid cells. The numbers of acid-fast M. leprae in the peripheral sites were examined by slit smear and in biopsies of matched leprosy lesions taken before and after IL-2 administration. Within 2 mo, slit smears showed a 0.5 log or greater reduction in 12 of 14 patients, with a mean for all patients tested of 0.5 log units. Biopsy specimens showed a 1 log unit or greater reduction in the bacterial index (B.I.) in 6 of 14 patients. Historical controls in this Nepalese population showed a 0.5 log unit reduction after multidrug therapy over a period of 12 mo. Thus, after 8 d of IL-2 injections, a fivefold reduction in B.I. was observed during the first 2 mo of the study. Antibody levels against M. leprae phenolic glycolipid 1 (PGL-1) and lipoarabinomanan B were markedly elevated after IL-2 injections, while PGL-1 antigen levels were reduced. We conclude that the administration of rIL-2 has had a significant effect in decreasing the total body burden of M. leprae.(ABSTRACT TRUNCATED AT 400 WORDS)

Role of adherent T cells and of B cells in the immune response to purified protein derivative of tuberculin

1979 ◽  
Vol 9 (4) ◽  
pp. 307-311 ◽  
Author(s):  
Mario P. Arala-Chaves ◽  
Maria T. Porto ◽  
Lapsly Hope ◽  
H. Hugh Fudenberg
Keyword(s):  
Immune Response ◽  
T Cells ◽  
B Cells ◽  
Purified Protein Derivative

scholarly journals Shared Transcriptional Control of Innate Lymphoid Cell and Dendritic Cell Development

2019 ◽  
Vol 35 (1) ◽  
pp. 381-406 ◽  
Author(s):  
Prachi Bagadia ◽  
Xiao Huang ◽  
Tian-Tian Liu ◽  
Kenneth M. Murphy
Keyword(s):  
Immune Response ◽  
Innate Immunity ◽  
T Cells ◽  
Dendritic Cells ◽  
Transcription Factors ◽  
Transcriptional Control ◽  
Lymphoid Cells ◽  
Transcriptional Networks ◽  
Innate Lymphoid Cell ◽  
Adaptive Immune

Innate immunity and adaptive immunity consist of highly specialized immune lineages that depend on transcription factors for both function and development. In this review, we dissect the similarities between two innate lineages, innate lymphoid cells (ILCs) and dendritic cells (DCs), and an adaptive immune lineage, T cells. ILCs, DCs, and T cells make up four functional immune modules and interact in concert to produce a specified immune response. These three immune lineages also share transcriptional networks governing the development of each lineage, and we discuss the similarities between ILCs and DCs in this review.

scholarly journals Kinetics of CD4+ and CD8+ Memory T-Cell Responses during Hepatitis C Virus Rechallenge of Previously Recovered Chimpanzees

2003 ◽  
Vol 77 (8) ◽  
pp. 4781-4793 ◽  
Author(s):  
Michelina Nascimbeni ◽  
Eishiro Mizukoshi ◽  
Markus Bosmann ◽  
Marian E. Major ◽  
Kathleen Mihalik ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Hepatitis C ◽  
T Cell ◽  
T Cell Responses ◽  
Rt Pcr ◽  
Cell Responses ◽  
Ifn Γ ◽  
Cellular Immune ◽  
Kinetics Of

ABSTRACT The immunological correlates of hepatitis C virus (HCV)-specific immunity are not well understood. Antibodies to HCV structural proteins do not appear to play a key role in clearance of the virus and do not persist after recovery. Here, we studied the kinetics of the cellular immune responses of three HCV-recovered chimpanzees during rechallenge with increasing doses of homologous HCV. Although HCV envelope antibodies remained undetectable throughout the rechallenge, all animals mounted rapid HCV-specific T-cell responses. The pattern of the cellular immune response in blood and liver correlated with the virological outcome. The animal that most rapidly cleared circulating HCV as determined by nested reverse transcription-PCR (RT-PCR) displayed the most vigorous and sustained response of gamma interferon (IFN-γ)-producing and proliferating CD4+ T cells in the blood. Vigorous CD4+ T-cell proliferation during viremia was followed by an increased frequency and a phenotypic and functional change of the tetramer+ CD8+ T-cell population. The second animal cleared HCV initially with strong peripheral and intrahepatic CD4+ T-cell responses but experienced low-level HCV recrudescence 12 weeks later, when HCV-specific T cells became undetectable. The third animal maintained minute amounts of circulating HCV, detectable only by nested RT-PCR, in the face of a weak IFN-γ+ T-cell response. Collectively, the results suggest protective rather than sterilizing immunity after recovery from hepatitis C. The rate of HCV clearance following reexposure depends on the cellular immune response, the quality and quantity of which may vary among chimpanzees that recovered from HCV infection.

Host-Microbiota Interactions in the Intestine

2015 ◽  
Vol 33 (2) ◽  
pp. 131-136 ◽  
Author(s):  
Charles O. Elson ◽  
Katie L. Alexander
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Adaptive Immunity ◽  
Bacterial Species ◽  
Critical Role ◽  
Effector T Cells ◽  
Lymphoid Cells ◽  
Mucosal Barrier ◽  
Microbiota Composition ◽  
Immune Mediated

The comprehensive collection of bacterial species, termed microbiota, within human and other mammalian hosts has profound effects on both innate and adaptive immunity. Multiple host innate mechanisms contribute to intestinal homeostasis, including epithelial production of protective mucin layers maintaining spatial segregation in the intestine as well as epithelial cell secretion of a broad range of antimicrobial peptides. Additionally, epithelial cells employ autophagy to contain and eliminate invading bacteria; interestingly, genetic variants in specific autophagy genes are linked to susceptibility to Crohn's disease. Innate lymphoid cells, which rapidly respond to cytokine and microbial signals, have emerged as important regulators of the intestinal immune response to the microbiota. With regard to adaptive immunity, specific microbial species stimulate induction of regulatory T cells while others induce effector T cells within the gut. Such stimulation is subject to dysregulation during inflammation and disease, contributing to ‘dysbiosis' or an abnormal microbiota composition that has been associated with a variety of immune-mediated inflammatory disorders, including celiac disease. The microbiota communicates with the immune system and vice versa; thus, an abnormal microbiota composition likely translates into an altered host immune response, though the exact mechanisms of such are not yet clear. Immunoglobulin A plays a critical role in limiting bacterial access to the host and in maintaining mutualism with the microbiota. Perturbation of the mucosal barrier via infection or other means can induce effector T cells reactive to the intestinal microbiota, and these cells can persist as memory cells for extended periods of time and potentially serve as pathogenic effector cells upon re-encounter with antigen. Health is associated with a diverse microbiota that functions to maintain the balance between T effector and T regulatory cells in the intestine. Whether dysbiosis can be reversed in immune-mediated disease, thus restoring health, is a question of intense interest for this active area of research.

Host-Derived IL-22 Limits Graft Versus Host Disease and Protects the Intestinal Stem Cell Niche

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 309-309
Author(s):  
Alan M. Hanash ◽  
Jarrod A Dudakov ◽  
Guoqiang Hua ◽  
Lauren F. Young ◽  
Maggie O'connor ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Small Intestine ◽  
Intestinal Epithelium ◽  
Critical Role ◽  
Hematopoietic Cells ◽  
Lymphoid Cells ◽  
Host Disease ◽  
Cell Niche

Abstract Abstract 309 Despite decades of intensive research, graft vs. host disease (GVHD) remains a major complication of allogeneic transplantation. Much progress has been made toward understanding GVHD pathophysiology and the mechanisms regulating the donor immune response, however no factors have been identified to regulate the response of transplant recipients to GVHD and its concomitant damage. Furthermore, virtually all strategies available to reduce clinical GVHD do so by limiting the donor immune system at the expense of therapeutic graft vs. leukemia/lymphoma (GVL) responses. IL-22 is a recently characterized cytokine that is produced by both helper T cells and innate lymphoid cells (ILC). Expression of its receptor (IL-22R) is generally limited to epithelial and other non-hematopoietic cells, and it has demonstrated a protective role for intestinal epithelium during experimental colitis, providing a signal for intestinal epithelial cell survival, proliferation, and wound healing. We investigated the role of IL-22 in GVHD during MHC-mismatched C57BL/6 (B6) into BALB/c murine bone marrow transplantation (BMT). Elimination of IL-22 with anti-IL-22 neutralizing antibody lead to increased GVHD mortality post-BMT in comparison to isotype control (p<.01). Interestingly, use of IL-22 knockout (KO) donor marrow or T cells had no impact on survival or on the ability to clear A20 lymphoma post-BMT, but IL-22 KO BMT recipients demonstrated significantly increased mortality during GVHD (p<.01). The critical role of recipient-derived IL-22 was confirmed in a minor antigen-mismatched LP into B6 BMT model (Figure 1). IL-22 KO recipients again demonstrated significantly increased mortality during GVHD (p<.001) and histopathologic evidence of GVHD in the small (p<.01) and large (p<.001) intestine and liver (p<.001). Furthermore, BMT into hematopoietic IL-22 KO chimeras also demonstrated increased GVHD mortality (p<.05) and clinical scoring (p<.001), indicating that the source of protective IL-22 is residual host-derived radio-resistant hematopoietic cells. IL-22 ELISA on tissue homogenates following BMT with wild type donors and recipients indicated that IL-22 levels are increased three weeks post-BMT in both small and large intestine (p<.05), as well as following sublethal radiation without transplantation (p<.05 small intestine; p<.01 large) in comparison to normal controls. However, IL-22 was significantly reduced in both tissues during GVHD (2 weeks post-BMT in small intestine, Figure 2A; 3 weeks post-BMT in large, p<.05), suggesting that IL-22 was produced by residual host hematopoietic cells that were being eliminated during GVHD. Consistent with this, we identified IL-22-producing host ILC (CD45+CD3−RORg+) in small intestine lamina propria two weeks post-BMT, whereas no IL-22 production could be identified in CD3+ or RORg− subsets, and these IL-22-producing ILC were significantly reduced during GVHD (p<.05, Figure 2B). Interestingly, although host IL-22 deficiency was associated with increased GVHD morbidity, mortality, and pathology, no major differences were observed in donor lymphocyte infiltration of recipient intestines, frequencies of donor lymphoid subsets, or donor T cell inflammatory cytokines post-BMT. In contrast, IL-22R expression on recipient intestinal epithelium was increased post-BMT, and GVHD in IL-22 KO recipients led to increased damage of the intestinal epithelium as measured by FITC-dextran absorption (p<.05). Additionally, IL-22R expression was identified by immunohistochemistry in intestinal crypts where the stem/progenitor cell niche is located, and use of LGR5-LacZ reporter mice indicated that intestinal stem cells (ISC) were indeed targets of GVHD. Finally, histologic assessment of the ISC niche demonstrated exacerbated loss of both ISC (p<.001, Figure 2C) and Paneth cells (p<.05) in IL-22 KO mice during GVHD. In summary, IL-22 is produced post-BMT by host ILC that are eliminated during GVHD, and IL-22 deficiency increases GVHD morbidity and mortality. While IL-22 deficiency did not significantly alter the donor immune response, it did lead to increased GVHD pathology, loss of epithelial integrity, and damage to the ISC niche. IL-22 is thus critical for protection of host epithelium during GVHD but is not involved in GVL. This may be exploited in the future to reduce clinical GVHD without limiting the curative potential of the transplant. Disclosures: Fouser: Pfizer: Employment.

scholarly journals A NOVEL LANGERIN EXPRESSING TYPE 2-CONVENTIONAL DENDRITIC CELL IS SIGNIFICANTLY DECREASED IN CROHN’S DISEASE

2021 ◽  
Vol 27 (Supplement_1) ◽  
pp. S32-S33
Author(s):  
Chloe Doyle ◽  
Kirstie Bertram ◽  
Jake Rhodes ◽  
Anthony Cunningham ◽  
Grahame Ctercteko ◽  
...  
Keyword(s):  
T Cells ◽  
Crohn’S Disease ◽  
Immune System ◽  
Dendritic Cell ◽  
Crohn's Disease ◽  
Mononuclear Phagocytes ◽  
Lymphoid Cells ◽  
T Helper 17 ◽  
Intestinal Immune System

Abstract Crohn’s disease is a chronic relapsing auto-inflammatory condition of the gastrointestinal tract that primarily affects young individuals with an increasing incidence rate. There is still no cure for Crohn’s disease and current treatment-options are limited to controlling inflammatory molecules such as TNF. Unfortunately, these biologics can produce significant side effects and not all patients respond to anti-TNF treatment. New treatments are therefore urgently needed. Targeting the cells and molecules of the immune system still represents the most promising approach which is why we have conducted an in-depth study of the immune cells and molecules associated with a healthy intestinal immune system and compared that to what is happening in Crohn’s disease. Our group has privileged access to large human ileum explants as well as draining lymph node samples isolated from patients undergoing colorectal surgery to remove Crohn’s affected tissue. We have designed and optimised enzymatic tissue digestion protocols to isolate these cells in an immature state with minimal receptor cleavage. We have also developed high-parameter flow and mass cytometry panels to comprehensively identify and characterise all known subsets of mononuclear phagocytes (MNP), innate lymphoid cells, mucosal-associated invariant T cells, natural killer cells and T and B lymphocytes. We have discovered that the newly described Langerin+ type 2-conventional dendritic cell (cDC2) is significantly decreased in Crohn’s affected ileum compared to healthy ileum. Furthermore, we have shown this decrease corresponds with lower TGF-b levels, a known driver of Langerin expression. After 7 days of co-culture, sorted Langerin+ cDC2 induced significantly higher levels of IL-17 and IL-22 in allogenic naïve CD4+ T cells compared to other MNP subsets, including cDC2 which did not express Langerin. These differentiated T cells expressed high levels of RORt and aryl hydrocarbon receptor (AHR) – transcription factors that are associated with CD4+ T helper 17 cells, implying that they may play a crucial role in intestinal barrier repair and regeneration that is absent in Crohn’s disease. Together these results suggest that Langerin+ cDC2 may have an anti-inflammatory role in human tissue and their reduction in Crohn’s disease may contribute to the pathogenesis of this disease, highlighting a potential therapeutic target for Crohn’s disease.

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