Up-regulated expression in nonhematopoietic tissues of the BCL2A1-derived minor histocompatibility antigens in response to inflammatory cytokines: relevance for allogeneic immunotherapy of leukemia

T cells directed against hematopoietic-restricted minor histocompatibility antigens (mHags) may mediate graft-versus-leukemia (GVL) reactivity without graft-versus-host disease (GVHD). Recently, the HLA-A24–restricted mHag ACC-1 and the HLA-B44–restricted mHag ACC-2 encoded by separate polymorphisms within the BCL2A1 gene were characterized. Hematopoietic-restricted expression was suggested for these mHags. We demonstrate BCL2-related protein A1 (BCL2A1) mRNA expression in mesenchymal stromal cells (MSCs) that was up-regulated by the inflammatory cytokines tumor necrosis factor α (TNF-α) and/or interferon γ (IFN-γ). Analysis of cytotoxicity and IFN-γ production illustrated that ACC-2–specific T cells did not recognize untreated MSCs or IFN-γ–treated MSCs but showed specific recognition and killing of MSCs treated with TNF-α plus IFN-γ. We hypothesize that under steady-state circumstances BCL2A1-specific T cells may exhibit relative specificity for hematopoietic tissue, but reactivity against nonhematopoietic cells may occur when inflammatory infiltrates are present. Thus, the role of BCL2A1-specific T cells in differential induction of GVL reactivity and GVHD may depend on the presence of inflammatory responses that may occur during GVHD.

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T Cell–mediated Pathology in Two Models of Experimental Colitis Depends Predominantly on the Interleukin 12/Signal Transducer and Activator of Transcription (Stat)-4 Pathway, but Is Not Conditional on Interferon γ Expression by T Cells

Journal of Experimental Medicine ◽

10.1084/jem.187.8.1225 ◽

1998 ◽

Vol 187 (8) ◽

pp. 1225-1234 ◽

Cited By ~ 207

Author(s):

Stephen J. Simpson ◽

Samir Shah ◽

Martina Comiskey ◽

Ype P. de Jong ◽

Baoping Wang ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Experimental Colitis ◽

Interferon Γ ◽

Adoptive Cell Transfer ◽

Interleukin 12 ◽

Signal Transducer ◽

Immunodeficient Mice ◽

Tnf Α ◽

Ifn Γ

The requirements for interleukin (IL)-12/signal transducer and activator of transcription (Stat)-4 signaling and induction of T cell–specific interferon (IFN)-γ expression in the development of T helper cell (Th)1–type pathology were examined in two different models of experimental colitis. In each model, abnormal reconstitution of the T cell compartment in immunodeficient mice by adoptive cell transfer leads to a wasting syndrome and inflammation of the colon, induced by IFN-γ and tumor necrosis factor (TNF)-α–producing T cells. We show here that treatment with anti–IL-12 antibodies in one of the models, or reconstitution with T cells from Stat-4–deficient (Stat-4null) mice in both models resulted in a milder disease in the majority of recipient animals, compared with those that were left untreated or that had been reconstituted with wt cells. Protected mice in each group also harbored lower frequencies of IFN-γ–producing T cells than did diseased mice, suggesting that effects on wasting and colitis resulted from the attenuation of IFN-γ expression by T cells. To test whether the development of pathogenic T cells in the two colitis models was directly dependent on T cell–specific IFN-γ expression, IFN-γnull donors were used for T cell reconstitution in each system. Surprisingly, large numbers of IFN-γnull–reconstituted mice developed wasting and colitis, which in many cases was of comparable severity to that seen in animals reconstituted with wt cells. Furthermore, T cells from these animals expressed TNF-α, demonstrating that they had retained the ability to produce another proinflammatory cytokine. Taken together, these results demonstrate that in some forms of chronic experimental colitis the development of pathogenic T cells is influenced predominantly, though not exclusively, by IL-12 via the actions of Stat-4 proteins. Furthermore, our data suggest that in the models of colitis studied here the effects of IL-12/Stat-4 or other Th1 promoting pathways are not limited to the induction of IFN-γ gene expression in T lymphocytes.

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Cytokine induction after Epstein-Barr virus infection of peripheral T-lymphocytes in vitro

Asian Biomedicine ◽

10.2478/abm-2010-0008 ◽

2010 ◽

Vol 4 (1) ◽

pp. 69-77

Author(s):

Putrada Ninla-aesong ◽

Jintana Pradutkanchana ◽

Kusumarn Noipha ◽

Winyou Mitarnun

Keyword(s):

T Cells ◽

T Cell ◽

Interferon Γ ◽

Cell Infection ◽

Barr Virus ◽

Cytokine Induction ◽

Tnf Α ◽

Ifn Γ ◽

Epstein Barr

Abstract Background: Although the presence of Epstein-Barr virus (EBV) in different T-cell malignancies has been widely reported, there is very few data available for EBV infection of normal T cells. This leads to the lack of knowledge on the early events after T cell infection. Objective: Investigate the early events occurring after normal human peripheral T-cells are infected with EBV in vitro. Methods: T-cells were treated with EBV in vitro. The expression of tumor necrosis factor- α (TNF-α) mRNA were determined using reverse-transcription (RT)-PCR, and the level of TNF-α and interferon- γ (IFN-γ) in the culture supernatant were measured using ELISA. The effect of virus inactivation on cytokine induction from T-cells was also determined. Results: At the beginning of T cell infection by EBV, the expression of several lytic EBV transcripts (BALF5, BcLF1, and BLLF1) were observed using RT-PCR. This indicated the susceptibility of in vitro EBV infection and the entering lytic cycle of EBV-infected T-cells. The interactions of EBV with T-cells lead to induction of inflammatory cytokines, tumour necrosis factor- α (TNF-α) and interferon- γ (IFN-γ), production from the T-cells. Inactivation of the virus by UV irradiation eliminated the TNF-α and IFN-γ induction by EBV, suggesting the involvement in the expression of viral gene(s). Conclusion: This in vitro analysis demonstrated the cytokine induction by EBV after primary infection of T-cells.

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The effect of hemantane on the level of pro-inflammatory cytokines in the nigrocaudate complex of the brain of mice with experimental parkinsonism

Nauchno-prakticheskii zhurnal «Patogenez» ◽

10.25557/2310-0435.2021.02.45-49 ◽

2021 ◽

pp. 45-49

Author(s):

Н.А. Воронина ◽

В.Г. Кучеряну ◽

Л.А. Ветрилэ ◽

В.В. Голоборщева ◽

И.Г. Капица ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Clinical Stage ◽

Late Phase ◽

Brain Structures ◽

Interferon Γ ◽

Nigrostriatal System ◽

Enzyme Linked Immunosorbent Assay ◽

Tnf Α ◽

Ifn Γ ◽

Pro Inflammatory Cytokines

Целью данных исследований явилось изучение влияния гимантана (N-(2-адамантил)-гексаметиленимина гидрохлорида) на уровень провоспалительных цитокинов IL-1β, IL-6, интерферона-γ (ИФН-γ) и фактора некроза опухоли-α (ФНО-α) в нигрокаудатном комплексе мышей на ранней и поздней клинической фазе экспериментального паркинсонического синдрома (ПС), для выяснения его антипаркинсонического эффекта. Методы исследования: Раннюю и позднюю клиническую фазу ПС создавали у мышей линии C57BL/6J внутрибрюшинным введением пронейротоксина 1-метил-4-фенил-1,2,3,6-тетрагидропиридина (МФТП) в дозах 12 мг/кг или 20 мг/кг по 4 инъекции с интервалом 2 часа, соответственно. Гимантан вводили мышам внутрибрюшинным в дозе 20 мг/кг, предварительно каждый раз за 30 мин до введения МФТП. Содержание цитокинов в структурах мозга мышей определяли методом иммуноферментного анализа с использованием тест-систем производства «Cloud-Clone Corporation», США и считывающего устройства «ИФА-reader» прибора «ImmunoChem-2100», США. Результаты: Показано, что уровень IL-1β, IL-6, ИФН-γ и ФНО-α в нигрокаудатном комплексе мозга мышей возрастает как на ранней, так и на поздней фазах развития ПС. Предварительное применение гимантана снижало в нигрокаудатном комплексе мышей содержание цитокинов IL-1β, ИФН-γ и ФНО-α на ранней фазе, и только одного из 4 изученных (IL-6) - на поздней фазе развития ПС. Предполагается, что антипаркинсонический эффект гимантана на ранней клинической стадии МФТП-индуцированного ПС осуществляется, в том числе, за счёт снижения уровня провоспалительных цитокинов в нигростриатной системе, предупреждая снижение жизнеспособности дофаминергических нейронов. The aim of this work was to study the effect of Hemantane (N-(2-adamantyl)-hexamethyleneimine hydrochloride) on the level of pro-inflammatory cytokines IL-1β, IL-6, interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α) in the nigrocaudate complex of mice in early and late clinical phases of experimental Parkinsonian syndrome (PS) to elucidate its antiparkinsonian effect. Material and methods: The early and late clinical phases of PS were created in C57BL / 6J mice by 4 intraperitoneal injections at 2-h intervals of a proneurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), at a dose of 12 mg/kg or 20 mg/kg. Hemantane was injected intraperitoneally at a dose of 20 mg/kg 30 min before each MPTP administration. Concentrations of cytokines in mouse brain structures were measured by enzyme-linked immunosorbent assay (ELISA) using Cloud-Clone Corporation (USA) test systems and an ImmunoChem-2100 (USA) ELISA reader. Results: Concentrations of IL-1β, IL-6, IFN-γ, and TNF-α in the nigrocaudate complex were increased both in the early and late phases of PS. Prior administration of hemantane reduced the content of IL-1β, IFN-γ, and TNF-α in the nigrocaudate complex at the early phase and the content of only one of the 4 studied cytokines (IL-6) at the late phase of PS. It was assumed that the antiparkinsonian effect of hemantane at the early clinical stage of MPTP-induced PS involves a decrease in proinflammatory cytokines in the nigrostriatal system, which prevents the impairment of the viability of dopaminergic neurons.

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Highly functional virus-specific cellular immune response in asymptomatic SARS-CoV-2 infection

10.1101/2020.11.25.399139 ◽

2020 ◽

Author(s):

Nina Le Bert ◽

Hannah E Clapham ◽

Anthony T Tan ◽

Wan Ni Chia ◽

Christine YL Tham ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

Inflammatory Cytokines ◽

T Cell Activation ◽

Cellular Immune Response ◽

Cell Activation ◽

Tnf Α ◽

Specific Cellular Immune Response ◽

Ifn Γ ◽

Cellular Immune

AbstractThe efficacy of virus-specific T cells in clearing pathogens involves a fine balance between their antiviral and inflammatory features. SARS-CoV-2-specific T cells in individuals who clear SARS-CoV-2 infection without symptoms or disease could reveal non-pathological yet protective characteristics. We therefore compared the quantity and function of SARS-CoV-2-specific T cells in a cohort of asymptomatic individuals (n=85) with that of symptomatic COVID-19 patients (n=76), at different time points after antibody seroconversion. We quantified T cells reactive to structural proteins (M, NP and Spike) using ELISpot assays, and measured the magnitude of cytokine secretion (IL-2, IFN-γ, IL-4, IL-6, IL-1β, TNF-α and IL-10) in whole blood following T cell activation with SARS-CoV-2 peptide pools as a functional readout. Frequencies of T cells specific for the different SARS-CoV-2 proteins in the early phases of recovery were similar between asymptomatic and symptomatic individuals. However, we detected an increased IFN-γ and IL-2 production in asymptomatic compared to symptomatic individuals after activation of SARS-CoV-2-specific T cells in blood. This was associated with a proportional secretion of IL-10 and pro-inflammatory cytokines (IL-6, TNF-α and IL-1β) only in asymptomatic infection, while a disproportionate secretion of inflammatory cytokines was triggered by SARS-CoV-2-specific T cell activation in symptomatic individuals. Thus, asymptomatic SARS-CoV-2 infected individuals are not characterized by a weak antiviral immunity; on the contrary, they mount a robust and highly functional virus-specific cellular immune response. Their ability to induce a proportionate production of IL-10 might help to reduce inflammatory events during viral clearance.

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Acupuncture Can Regulate the Distribution of Lymphocyte Subsets and the Levels of Inflammatory Cytokines in Patients With Mild to Moderate Vascular Dementia

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.747673 ◽

2021 ◽

Vol 13 ◽

Author(s):

Hui Zhi ◽

Yao Wang ◽

Shichen Chang ◽

Pan Pan ◽

Zhenzhen Ling ◽

...

Keyword(s):

T Cells ◽

Immune Function ◽

Vascular Dementia ◽

Inflammatory Cytokines ◽

Peripheral Blood ◽

Lymphocyte Subsets ◽

Acupuncture Treatment ◽

Normal Group ◽

Tnf Α ◽

Ifn Γ

Background: Vascular dementia (VD) is the second most common type of dementia after Alzheimer’s disease, but there is a lack of definitive treatment for VD. Acupuncture treatment is effective in improving the cognitive impairment and behavioral capacity of patients with VD. In recent years, more studies indicated that peripheral inflammation and abnormal peripheral immune function may aggravate neuroinflammation and cognitive dysfunction. However, there are few studies about the acupuncture and the abnormal peripheral immune function of VD. Also, few studies concern the regulating effect of acupuncture on peripheral immunity of patients with VD.Objective: The aim of this study was to explore the effect of the “sanjiao” acupuncture method on peripheral immunity of patients with mild to moderate VD.Methods: A total of 30 patients with VD were involved in the acupuncture group (AG), which was treated with the “sanjiao” acupuncture method once a day for six times a week and lasted for 12 weeks, and 30 healthy elderly people were assigned to the normal group (NG), which had no treatment. The distribution of lymphocyte subsets and the levels of some inflammatory cytokines in the peripheral blood of subjects were evaluated using the flow cytometry (FCM) and the enzyme-linked immunosorbent assay (ELISA).Results: A total of 60 subjects were involved in this study, while 58 subjects completed the entire trial. Before treatment, the levels of CD3+ T, CD4+ T cells, CD4+/CD8+, Tregs, B cells, IFN-γ, and IL-10 in patients with VD were significantly decreased compared with the normal group (all P < 0.05 or P < 0.01). The level of TNF-α in peripheral blood of patients with VD was significantly increased (P < 0.01). After acupuncture treatment, the levels of CD3+ T, CD4+ T cells, and IFN-γ were significantly increased (all P < 0.05 or P < 0.01). The level of TNF-α was significantly decreased (P < 0.01). The proportion of Tregs was increased (P < 0.01), but it was still lower than that of the normal group (P < 0.05).Conclusion: The acupuncture method can increase the proportion of CD3+, CD4+ T cells, and Tregs in peripheral blood of patients with VD. And, it reduces the levels of pro-inflammatory factor TNF-α, which achieves the anti-inflammatory effects and immunostimulation. It suggests that acupuncture can improve the peripheral immune dysfunction of patients with VD by regulating the distribution of lymphocyte subsets and the levels of inflammatory cytokines.Clinical Trial Registration: [www.chictr.org.cn], identifier [ChiCTR-IOR-17012052].

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IRGM3 Contributes to Immunopathology and Is Required for Differentiation of Antigen-Specific Effector CD8+T Cells in Experimental Cerebral Malaria

Infection and Immunity ◽

10.1128/iai.02701-14 ◽

2015 ◽

Vol 83 (4) ◽

pp. 1406-1417 ◽

Cited By ~ 5

Author(s):

Jintao Guo ◽

James A. McQuillan ◽

Belinda Yau ◽

Gregory S. Tullo ◽

Carole A. Long ◽

...

Keyword(s):

T Cells ◽

Cerebral Malaria ◽

Inflammatory Cytokines ◽

Inflammatory Responses ◽

Type I ◽

Experimental Cerebral Malaria ◽

Content Type ◽

Cytokines And Chemokines ◽

Specific Effector ◽

Ifn Γ

Gamma interferon (IFN-γ) drives antiparasite responses and immunopathology during infection withPlasmodiumspecies. Immunity-related GTPases (IRGs) are a class of IFN-γ-dependent proteins that are essential for cell autonomous immunity to numerous intracellular pathogens. However, it is currently unknown whether IRGs modulate responses during malaria. We have used thePlasmodium bergheiANKA (PbA) model in which mice develop experimental cerebral malaria (ECM) to study the roles of IRGM1 and IRGM3 in immunopathology. Induction of mRNA forIrgm1andIrgm3was found in the brains and spleens of infected mice at times of peak IFN-γ production.Irgm3−/−but notIrgm1−/−mice were completely protected from the development of ECM, and this protection was associated with the decreased induction of inflammatory cytokines, as well as decreased recruitment and activation of CD8+T cells within the brain. Although antigen-specific proliferation of transferred CD8+T cells was not diminished compared to that of wild-type recipients following PbA infection, T cells transferred intoIrgm3−/−recipients showed a striking impairment of effector differentiation. Decreased induction of several inflammatory cytokines and chemokines (interleukin-6, CCL2, CCL3, and CCL4), as well as enhanced mRNA expression of type-I IFNs, was found in the spleens ofIrgm3−/−mice at day 4 postinfection. Together, these data suggest that protection from ECM pathology inIrgm3−/−mice occurs due to impaired generation of CD8+effector function. This defect is nonintrinsic to CD8+T cells. Instead, diminished T cell responses most likely result from defective initiation of inflammatory responses in myeloid cells.

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"Tien-Hsien Liquid" Can Modulate Antigen-Stimulated Cytokine Production by T-Cells Isolated from Patients with Recurrent Aphthous Ulcerations

The American Journal of Chinese Medicine ◽

10.1142/s0192415x05003168 ◽

2005 ◽

Vol 33 (04) ◽

pp. 559-571 ◽

Cited By ~ 6

Author(s):

Andy Sun ◽

Jean-San Chia ◽

Won-Bo Wang ◽

Chun-Pin Chiang

Keyword(s):

T Cells ◽

Mononuclear Cells ◽

Cytokine Production ◽

Interferon Γ ◽

Enzyme Linked Immunosorbent Assay ◽

Peripheral Blood Mononuclear ◽

Tnf Α ◽

Ifn Γ ◽

Factor Α ◽

Necrosis Factor

Recurrent aphthous ulcerations (RAU) represent a common oral mucosal disease with altered humoral and cellular immunities. Tien-Hsien liquid (THL) is an extract of Chinese medicinal herbs with immunomodulating effects. Our previous study found that THL can modulate the antigen-stimulated proliferative response of peripheral blood mononuclear cells and T-cells isolated from RAU patients. In this study, we further tested whether THL can modulate the antigen-stimulated cytokine production by T-cells isolated from RAU patients. To achieve this goal, T-cells isolated from 19 RAU patients were incubated with phytohemagglutinin (PHA), glutaraldehyde-inactivated tetanus toxoid (TT), glucosyltransferase D (GtfD), or antigens of Streptococcus mutans in the presence or absence of THL. The levels of interleukin (IL)-2, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), IL-6, or IL-10 in the supernatants of T-cell cultures were measured by cytokine enzyme-linked immunosorbent assay (ELISA) kits. We found that THL significantly increased the PHA- or TT-stimulated TNF-α, IL-6, and IL-10 production by T-cells isolated from RAU patients. However, THL could also significantly decrease the TT-stimulated IL-2 production, the GtfD-stimulated IL-2, TNF-α, IL-6 and IL-10 production, and the S. mutans-stimulated IFN-γ, TNF-α, and IL-10 production by T-cells isolated from RAU patients. These results indicate that THL can modulate the antigen-stimulated cytokine production by T-cells isolated from RAU patients. Because RAU is probably a Thl-mediated disease with elevated levels of IL-2, IFN-γ, TNF-α and IL-6 in either the patient's sera or oral lesions and these increased levels of cytokines can be reduced by THL, we suggest that THL may be a potential immunoceutical agent for treatment of RAU.

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Lymphocyte-derived interferon-γ mediates ischemia-reperfusion-induced leukocyte and platelet adhesion in intestinal microcirculation

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.90495.2008 ◽

2009 ◽

Vol 296 (3) ◽

pp. G659-G663 ◽

Cited By ~ 14

Author(s):

Mohammad Osman ◽

Janice Russell ◽

D. Neil Granger

Keyword(s):

T Cells ◽

B Cells ◽

B Cell ◽

Adoptive Transfer ◽

Inflammatory Responses ◽

Leukocyte Adhesion ◽

Ischemia Reperfusion ◽

Interferon Γ ◽

Intestinal Microcirculation ◽

Ifn Γ

Although previous studies have implicated lymphocytes in the gut microvascular and inflammatory responses to ischemia-reperfusion (I/R), the lymphocyte population and lymphocyte-derived products that mediate these responses have not been defined. Platelet and leukocyte adhesion was measured in intestinal postcapillary venules of wild-type (WT) mice and mice genetically deficient in either CD4+ T cells (CD4−/−), CD8+ T cells (CD8−/−), B cells (B cell−/−), or interferon-γ (IFN-γ−/−) subjected to 45 min of ischemia and 4 h of reperfusion. The I/R-induced platelet and leukocyte recruitment responses were also evaluated following adoptive transfer of WT splenocytes into CD4−/−, CD8−/−, B cell−/−, and IFN-γ−/− mice. WT mice exposed to gut I/R exhibited significant increases in the adhesion of both platelets and leukocytes, compared with sham-WT mice. These blood cell adhesion responses to I/R were greatly attenuated in CD4−/−, CD8−/−, B cell−/−, and IFN-γ−/− mice. Adoptive transfer of WT splenocytes restored the WT responses to I/R in all mutants except the B cell−/− mice. These findings implicate both T and B cells and lymphocyte-derived IFN-γ as mediators of the proinflammatory and prothrombogenic phenotype assumed by intestinal microvessels after I/R.

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Pro and Anti-inflammatory Cytokine Production in CD4+ T Lymphocytes in Children with Asthma and Allergic Rhinitis Exposed to the Monocyte Locomotion Inhibitory Factor (MLIF)

Iranian Journal of Allergy Asthma and Immunology ◽

10.18502/ijaai.v17i4.98 ◽

2018 ◽

Author(s):

Sara Rojas-Dotor ◽

Adriana González-Hernández ◽

Francisco León-Aguilar ◽

Víctor Juárez-Téllez ◽

Patricia Gómez de León-Cruces

Keyword(s):

T Cells ◽

Allergic Rhinitis ◽

T Lymphocytes ◽

Inflammatory Cytokines ◽

Inhibitory Factor ◽

Expression Levels ◽

Tnf Α ◽

Children With Asthma ◽

Ifn Γ ◽

Anti Inflammatory

Entamoeba histolytica produces, in axenic culture, the monocytes locomotion inhibitory factor (MLIF), a oligopeptide with selective anti-inflammatory properties. We evaluated the effect of MLIF on the expression of pro- and anti-inflammatory cytokines in CD4+ T lymphocytes from children with asthma and allergic rhinitis. Twelve children with severe asthma, 12 children with allergic rhinitis and 6 healthy controls were recruited for this study between May and December 2016. CD4+ T cells were cultured for 24 h at 37°C, 5% CO2 in the presence of MLIF, 1-phorbol 12-myristate 13-acetate (PMA), MLIF+PMA or RPMI. Interleukin-10 (IL-10), IL-4, interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) expression levels were measured in the supernatants of T-cell cultures using the enzyme-linked immunosorbent assay (ELISA). Pro- and anti-inflammatory cytokines were inhibited by MLIF (IFN-γ p=0.0036, TNF-α p<0.001, IL-4 p=0.0082) in asthmatic patients, however IFN-γ was not significantly inhibited (NS) in patients with allergic rhinitis when compared to the RPMI group. In CD4+ T cells treated with PMA+MLIF, the expression levels of IFN-γ, TNF-α and IL-4 were strongly inhibited (p<0.001, p<0.001 and p<0.0094), compared to PMA treatment alone, for both, rhinitis and asthma. IL-10 expression was not affected by MLIF in neither of the two diseases. We conclude that MLIF alters the pro/anti-inflammatory balance and induces inhibition of IL-4, IFN-γ and TNF-α, but does not affect IL-10.

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Donor APCs Promote Gvhd in MHC-Mismatched Transplants by Indirectly Presenting Host Minor Histocompatibility Antigens.

Blood ◽

10.1182/blood.v114.22.689.689 ◽

2009 ◽

Vol 114 (22) ◽

pp. 689-689

Author(s):

Xiaojian Wang ◽

Catherine Martone ◽

Anthony Demetris ◽

Jennifer McNiff ◽

Warren D. Shlomchik

Keyword(s):

T Cells ◽

T Cell ◽

Acute Gvhd ◽

Late Onset ◽

Chronic Gvhd ◽

Organ Distribution ◽

Cd4 Cells ◽

Histocompatibility Antigens ◽

Minor Histocompatibility Antigens ◽

Ifn Γ

Abstract Abstract 689 In MHC-mismatched allogeneic bone marrow/stem cell transplantation (alloBMT), T cells that at least in-part recognize the allogeneic MHC are likely the dominant mediators of acute GVHD. This would explain why far fewer T cells induce acute GVHD in MHC-mismatched as opposed to MHC-matched alloBMT. However, despite this difference, in human recipients of haploidentical allografts, the organ distribution and histologic appearance of GVHD, especially chronic GVHD, are similar. Moreover, late-onset GVHD in MHC-mismatched alloBMT occurs when recipient antigen presenting cells (APCs) have been replaced by donor APCs. We therefore investigated how indirect presentation of host minor histocompatibility antigens (miHAs) by donor APCs contributes to GVHD. To test this, we employed the MHC/miHA mismatched B6 (H-2b) (right arrow) BALB/c (H-2d) strain pairing. We compared GVHD in irradiated BALB/c mice that were reconstituted with B6 CD4 cells and either B6 BM or B6 MHCII-/- BM. We reasoned that if BALB/c miHAs presented by donor B6 APCs were important, GVHD would be reduced in recipients of MHCII-/- BM. As measured by weight loss and survival, this was indeed the case. However, it was possible that receiving MHCII-/- donor BM reduced GVHD for reasons unrelated to the presentation of BALB/c miHAs. To address this we compared GVHD in irradiated B6.C (H-2d) recipients of B6 CD4 cells and either B6 or B6 MHCII-/- BM. This strain pairing shares the same MHC mismatch as does the B6(right arrow)BALB/c model, but lacks miHAs except those encoded by the congenic H-2d region. In contrast to the prior experiments, B6.C recipients of MHCII-/- or wild type BM developed similar GVHD. To further define indirect-presentation of miHAs in MHC/miHA-mismatched alloBMT, we used B6 Marilyn CD4+ T cell receptor transgenic T cells that recognize an IAb-restricted peptide derived from the male DBY protein. Male or female BALB/c mice were irradiated and reconstituted with female B6 BM and female polyclonal B6 CD4 cells along with graded numbers of Marilyn T cells. At day 7 and 14 post transplant Marilyn cells expanded at least 1000-fold greater in male than in female recipients. Marilyn T cell expansion was similar when male antigen was restricted to hematopoietic or nonhematopoietic cells. There was little expansion of Marilyn cells in male BALB/c mice if donor BM was MHCII-/-, confirming that expansion of Marilyn T cells depended on donor APCs presenting DBY. Indirectly primed Marilyn cells were functional as measured by IFN-γ production after restimulation by the DBY peptide in vitro. As we saw reduced GVHD in the B6 (right arrow) BALB/c model in recipients of MHCII-/- BM, we reasoned we should be able to detect polyclonal CD4 cells responding to host miHA presented by donor APCs. That was the case as we found an increase in DBY-reactive polyclonal CD4 cells by ELISPOT in male recipients as compared to female recipients at day 7 (1.5 fold for IFN-γ and TNF-αa). This difference was lost when donor BM was MHCII-/-. In summary, indirect presentation of host miHAs by donor APCs in MHC-mismatched alloBMT is surprisingly efficient and alloreactive CD4 cells that target host miHAs presented by donor APCs contribute to GVHD in MHC/miHA-disparate alloBMT. The generation of T cells that target host miHAs presented by donor APCs allows GVHD to persist even when host APCs that prime T cells that recognize the allogeneic MHC have been eradicated. This provides a mechanistic explanation for why late onset GVHD, including chronic GVHD, in MHC-mismatched alloBMT resembles that in MHC-matched alloBMT as both may target host miHAs indirectly presented by donor-derived APCs. These data also provide further rationale for targeting donor-derived APCs as a method for preventing and treating GVHD. Disclosures: No relevant conflicts of interest to declare.

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