Diagnostic and pathogenic features of calcifying pseudoneoplasm of the neuraxis

Calcifying pseudoneoplasm of the neuraxis (CAPNON) is a rare tumefactive lesion with unclear pathogenesis. It is diagnosed by pathological findings of the typical histological features that include granular amorphous cores with palisading spindle to epithelioid cells, variable fibrous stroma, foreign-body reaction with giant cells, and calcification/ossification occasionally with psammoma bodies. However, its histopathology may be variable and currently immunohistochemistry plays a limited role in its diagnosis and understanding the pathogenesis. In this study, we examined 6 cases of CAPNONs including 3 intracranial and 3 spinal epidural lesions (age range: 59–69 years; 3 males and 3 females). Immunohistochemistry revealed that all CAPNON cores contain abundant positive deposits of neurofilament protein (NFP), which was supported by electron microscopy finding of filaments (8–13 nm in diameter). In comparison, no NFP positivity was found in 5 psammomatous/metaplastic meningiomas or 7 intervertebral tissue lesions with calcification/ossification. In addition, CAPNON cellular areas showed variable numbers of CD8+ cytotoxic T-cells with less CD4+ T-cells and a decreased ratio of CD4/CD8+ cells, versus the intervertebral tissue lesions without CD8+ or CD4+ cells. Our findings suggest that NFP may be a principal constituent of CAPNONs, and thus involved in the pathogenesis of CAPNON. Given the decreased CD4/CD8 ratio, the pathogenic process of CAPNON is possibly immune- mediated.LEARNING OBJECTIVESThe presentation will enable the learner to: 1.Discuss histopathological features of calcifying pseudoneoplasm of the neuraxis (CAPNON) with variation of non-core components.2.Explore diagnostic and pathogenic roles of immunohistochemical markers including neurofilament protein and CD4/CD8 in CAPNON.

Download Full-text

Thyroid status regulates tumor microenvironment delineating breast cancer fate

Endocrine Related Cancer ◽

10.1530/erc-20-0277 ◽

2021 ◽

Author(s):

Helena Andrea Sterle ◽

Ximena Hildebrandt ◽

Matías Valenzuela Álvarez ◽

María Alejandra Paulazo ◽

Luciana Mariel Gutierrez ◽

...

Keyword(s):

Breast Cancer ◽

T Cells ◽

Tumor Microenvironment ◽

Lung Metastasis ◽

Cytotoxic T Cells ◽

Suppressor Cells ◽

Thyroid Status ◽

Cd8 Cells ◽

Regulatory T Lymphocytes ◽

Starting Point

The patient’s hormonal context plays a crucial role in the outcome of cancer. However, the association between thyroid disease and breast cancer risk remains unclear. We evaluated the effect of thyroid status on breast cancer growth and dissemination in an immunocompetent mouse model. For this, hyperthyroid and hypothyroid Balb/c mice were orthotopically inoculated with triple negative breast cancer 4T1 cells. Tumors from hyperthyroid mice showed increased growth rate and an immunosuppressive tumor microenvironment, characterized by increased IL-10 levels and decreased percentage of activated cytotoxic T cells. On the other hand, a delayed tumor growth in hypothyroid animals was associated with increased tumor infiltration of activated CD8+ cells and a high IFNγ/IL-10 ratio. Paradoxically, hypothyroid mice developed a higher number of lung metastasis than hyperthyroid animals. This was related to an increased secretion of tumor CCL2 and an immunosuppressive systemic environment, with increased proportion of regulatory T cells and IL-10 levels in spleens. A lower number of lung metastasis in hyperthyroid mice was related to the reduced presence of mesenchymal stem cells in tumors and metastatic sites. These animals also exhibited decreased percentages of regulatory T lymphocytes and myeloid-derived suppressor cells in spleens, but increased activated CD8+ cells and IFNγ/IL-10 ratio. Therefore, thyroid hormones modulate the cellular and cytokine content of the breast tumor microenvironment. The better understanding of the mechanisms involved in these effects could be a starting point for the discovery of new therapeutic targets for breast cancer.

Download Full-text

A study of the immune infiltrate and patient outcomes in esophageal cancer

Carcinogenesis ◽

10.1093/carcin/bgaa101 ◽

2020 ◽

Author(s):

Melissa J Conroy ◽

Susan A Kennedy ◽

Suzanne L Doyle ◽

Brian Hayes ◽

Maria Kavanagh ◽

...

Keyword(s):

T Cells ◽

Esophageal Cancer ◽

Patient Outcomes ◽

Immune Cell ◽

Cytotoxic T Cells ◽

Tissue Microarrays ◽

Stromal Compartment ◽

Cancer Subtypes ◽

Cd8 Cells ◽

Esophageal Tumors

Abstract Objectives Cancer patient outcomes and selection for novel therapies are heavily influenced by the immune contexture of the tumor microenvironment. Esophageal cancer is associated with poor outcomes. In contrast to colorectal cancer, where the immunoscore is increasingly used in prognostic staging, little is known about the immune cell populations in esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (SCC), and their clinical significance. Methods Tissue microarrays were constructed from resected tumor tissue of 72 EAC patients and 23 SCC patients. Immunohistochemical staining of CD3, CD8, CD56, CD68, CD45RO, CD69, IFN-γ, IL-10, IL-4, IL-17, TGF-β, FOXP3 and CD107a was performed. Positivity was examined in both the stromal and epithelial compartments. Statistical analysis was performed to identify differences in immune cell infiltration and functional phenotypes between cancer subtypes and tissue compartments. Results This study identified that esophageal tumors are enriched with CD45RO+ and CD8+ cells and such positivity is significantly higher in SCC compared with EAC. Furthermore, the expression of CD45RO positively correlates with that of CD8 within the tumors of both patient cohorts, suggesting a dominance of memory cytotoxic T cells. This is supported by strong positivity of degranulation marker CD107a in the stromal compartment of EAC and SCC tumors. Cytokine staining revealed a mixed pro- and anti-inflammatory profile within EAC tumors. Conclusions Esophageal tumors are enriched with memory cytotoxic T cells. Applying these measurements to a larger cohort will ascertain the clinical utility of assessing specific lymphocyte infiltrates in EAC and SCC tumors with regards to future immunotherapy use, patient prognosis and outcomes.

Download Full-text

The role of cytokines in the immunity development at helminthiasis

Russian Journal of Parasitology ◽

10.12737/23077 ◽

2016 ◽

Vol 3 (4) ◽

pp. 521-526

Author(s):

Гришина ◽

E. Grishina

Keyword(s):

T Cells ◽

Defense Mechanism ◽

Cytotoxic T Cells ◽

Relationship Building ◽

Practical Implementation ◽

Local Immunity ◽

Effector Cells ◽

Cd8 Cells ◽

Protection Mechanisms ◽

Low Efficiency

Intensive development of the parasitic diseases immunology in the past decade allows making a definite conclusion about the features of the immune response formation in helminthiasis and its key problems, such as short duration, low-efficiency and the ability to cause the development of immunopathological processes. Objective of research: The aim of this review was to identify most significant stages of helminthiasis immunogenesis wich can cause its low protective ability, and for which further comprehensive study of modern molecular biologists, geneticists, biochemists, immunologists and parasitologists should be held to clarify the immunopathology induction mechanisms and improve methods of prophylaxis, diagnosis and treatment of these diseases. Results and discussion. Studies have revealed that the main condition for relationship building in the system “parasite-host” is the presence of protection mechanisms in helminths against exposure to the host’s immune system and immunomodulation mechanisms up to the complete immunosuppression in host. Products of helminths vital activity, so-called secretory-excretory products (SEPs), as well as changed in the process of pathogenesis host proteins and cells become a powerful immune stimulus and activate mechanisms for general and local immunity. The following defense mechanism in helminthiasis is the most effective: participation of IgE antibodies class and IgG2 subclass which play a major role in the activation of cell adhesive activity; influence of cytotoxic T cells (T killer cells, CD8+ -cells); involvement of macrophages, activated with T-cells; work of induced effector cells (eosinophils, neutrophils, mast cells, platelets, etc.), and the results of natural killer (NK) and regulating Treg- lymphocyte population (CD4 + CD25 + -cells) activity. It was shown that helminthiasis is accompanied by oxidative stress, which is characterized by decreased activity of catalase, superoxide dismutase, and an increase of lipid peroxidation products, which may cause primary DNA damage underlying in gene and chromosomal mutations that is shown in prior studies. Parasites metabolites have a cytotoxic effect on somatic, generative and immune cells of host, causing the increase of apoptotic cells among them. Theoretical significance of the data on identification problems of helminthiases immunology is undoubted. Its practical implementation offers the significant increase in the effectiveness of helminthiasis prevention and control.

Download Full-text

LGG-22. EVALUATION OF IMMUNE AND GENOMIC CHARACTERISTICS IN PEDIATRIC OPTIC NERVE GLIOMA (ONG)

Neuro-Oncology ◽

10.1093/neuonc/noaa222.404 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii370-iii370

Author(s):

Ashley A Campbell ◽

Andrew M Silverman ◽

Hanna Moisander-Joyce ◽

Cheng-Chia Wu ◽

Mahesh Mansukhani ◽

...

Keyword(s):

T Cells ◽

Optic Nerve ◽

Medical Center ◽

Cytotoxic T Cells ◽

Additional Patient ◽

Molecular Characteristics ◽

Columbia University ◽

Optic Nerve Glioma ◽

Cd8 Cells ◽

Hla Dr

Abstract Pediatric optic nerve glioma (ONG) is a rare, sight-threatening tumor. We previously reported clinical, radiologic, histopathologic, and molecular characteristics of pediatric ONG patients treated at Columbia University Medical Center between 2000–2017. Here we evaluate this cohort and one additional patient using quantitative multiple immunofluorescence (qmIF) and next generation sequencing (NGS) using the Columbia Combined Cancer Panel (CCCP). For qmIF, 4 micron immuno-blank slides were stained for CD3, CD8, CD68, CD163, HLA-DR, and Olig2. QmIF images were analyzed and data were processed in R studio and compared based on tumor mutation and treatment history. QmIF failed in 1 case and CCCP failed in 2 cases. CCCP confirmed KIAA1549:BRAF fusions in 2 patients, identified NF1 in 2 patients, and demonstrated both a KIAA1549:BRAF fusion and SETD2 mutation in the added case. Qualitative analysis showed immune infiltrate across cases included macrophages (CD68+, 1.6–6.5% of all cells) and T cells (CD3+, 0.4% to 1.5%). Non-cytotoxic T cells (CD3+CD8-) comprised 60.7–100% of the T cell compartment. There was no difference when comparing mutation groups. However, patients who previously received radiation had increased CD3+, specifically CD3+CD8- cells compared to non-irradiated patients (p=0.01 and p<0.01, respectively) while CD3+CD8+ and CD68+ cells were not different between groups (p=0.49 and p=0.27, respectively). In summary, qmIF analysis showed increased tumor infiltration by non-cytotoxic T cells in previously irradiated pediatric ONG patients compared to non-irradiated patients, while there was no difference in macrophages of cytotoxic T cells. This type of analysis may be useful in designing immunotherapeutic strategies for pediatric ONG.

Download Full-text

159 Adoptively transferred CD8+ T cells that target neoantigen persist and regress melanomas to a greater extent than those that target self/tumor-antigen

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0159 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A173-A173

Author(s):

Amalia Rivera Reyes ◽

Megan Wyatt ◽

Connor Dwyer ◽

Hannah Knochelmann ◽

Aubrey Smith ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Fate ◽

Cd8 T Cells ◽

Tumor Antigen ◽

Cytotoxic T Cells ◽

List Type ◽

Secondary Tumor ◽

Affinity Peptide ◽

Self Antigen

BackgroundIn patients treated with immunotherapy, mechanisms underlying why some respond to or fail treatment are not fully understood. Higher tumor mutational burden is often correlated with better responses, because the immune system reacts more strongly against mutated antigens (versus self antigens) due to a higher affinity interaction with the T cell receptor. In adoptive T cell transfer therapy (ACT), engraftment and persistence of the T cells are critical to prolonged antitumor responses. It remains unclear whether the affinity of the interaction between tumor antigen and TCR alone impacts the engraftment and persistence of tumor-specific T cells post ACT.MethodsTo simulate this clinical scenario in mice, we used two different melanoma models: 1) B16F10 expressing a low affinity peptide (mgp100 = i.e. tumor/self-antigen), or 2) B16F10 expressing a higher affinity peptide (hgp100), which represents a neoantigen-expressing tumor.1 Pmel-1 CD8+ T cells expressing a TCR that recognizes gp100 were adoptively transferred into mice bearing B16F10 melanoma.ResultsWe posited that the function and persistence of adoptively transferred pmel-1 T cells would be increased in mice with neoantigen- compared to self- antigen expressing tumors. Indeed, we found that pmel-1 were less exhausted as well as engrafted and persisted far better in mice bearing tumors expressing neoantigens. Moreover, these large subcutaneous hot tumors shrank post ACT treatment and the animals survived long-term. Beneficial outcome was correlated with the appearance of vitiligo. Importantly, these cured mice were protected when rechallenged with a secondary tumor even after an intravenous rechallenge, implicating this ACT treatment mediates durable memory responses.ConclusionsHerein, we underscore how tumor antigen affinity can drastically change T cell fate. Future work will concentrate in exploring in depth the correlation of less differentiated cytotoxic T cells treating neo/self-antigen expressing melanomas mimicking a clinical setting.ReferenceHanada K, Yu Z, Chappell GR, Park AS, Restifo NP. An effective mouse model for adoptive cancer immunotherapy targeting neoantigens. JCI Insight 2019;4(10).

Download Full-text

Oral Salmonella: malaria circumsporozoite recombinants induce specific CD8+ cytotoxic T cells.

Journal of Experimental Medicine ◽

10.1084/jem.172.4.1083 ◽

1990 ◽

Vol 172 (4) ◽

pp. 1083-1090 ◽

Cited By ~ 139

Author(s):

A Aggarwal ◽

S Kumar ◽

R Jaffe ◽

D Hone ◽

M Gross ◽

...

Keyword(s):

T Cells ◽

Cytotoxic T Cells ◽

Oral Immunization ◽

Full Length ◽

Class I ◽

Peptide Epitope ◽

Cd8 Cells ◽

Flanking Sequences

Oral immunization with an attenuated Salmonella typhimurium recombinant containing the full-length Plasmodium berghei circumsporozoite (CS) gene induces protective immunity against P. berghei sporozoite challenge in the absence of antibody. We found that this immunity was mediated through the induction of specific CD8+ T cells since in vivo elimination of CD8+ cells abrogated protection. In vitro studies revealed that this Salmonella-P. berghei CS recombinant induced class I-restricted CD8+ cytotoxic T cells that are directed against the P. berghei CS peptide epitope spanning amino acids 242-253. This is the same peptide that previously was identified as the target of cytotoxic T lymphocytes (CTL) induced by sporozoite immunization. Salmonella-P. falciparum CS recombinants were constructed that contained either the full-length CS gene or a repeatless gene consisting of CS flanking sequences. Both of these vaccines were able to induce CD8+ CTL directed against P. falciparum CS peptide 371-390, which is identical to the target of CTL induced by sporozoites and vaccinia CS recombinants. These results directly demonstrate the ability of an intracellular bacteria such as Salmonella to induce class I-restricted CD8+ CTL and illustrate the importance of CD8+ CTL in immunity to malaria.

Download Full-text

Improved Homing of Antigen-Specific T Cells to Hodgkin’s Disease (HD) Tumor Cells by Forced Expression of CCR4 Receptor.

Blood ◽

10.1182/blood.v108.11.472.472 ◽

2006 ◽

Vol 108 (11) ◽

pp. 472-472

Author(s):

A. Di Stasi ◽

G. Dotti ◽

A. Foster ◽

L. Zhang ◽

Helen H. Heslop ◽

...

Keyword(s):

T Cells ◽

Tumor Cells ◽

Animal Studies ◽

Cytotoxic T Cells ◽

Antigen Specificity ◽

Activated T Cells ◽

Migration Assay ◽

Cd8 Cells ◽

Barr Virus

Abstract One crucial requirement for the success of any adoptive T cell transfer is that the effector T cells should migrate efficiently to the tumor site. Such an effect has been documented following adoptive transfer of Epstein-Barr virus specific cytotoxic T cells (EBV-CTLs). Antigenic stimulus from (normal and malignant) cells persistently infected with EBV led to expansion and sustained survival, and was also associated with activity against the EBV+ HD tumors. Since most HD patients have tumors that are EBV- but CD30+, we attempted to extend this approach by incorporating a CD30 chimeric receptor (CD30CAR) into the EBV-CTLs. Pre-clinical animal studies showed that CD30CAR+ EBV-CTLs readily migrated to EBV+/CD30+ tumors, but had limited capacity to localize to EBV−/CD30+ tumor cells. The likeliest explanation for this observation is that EBV- HD tumors produce the chemokine TARC, which attracts Th2 and regulatory T cells, but has little effect on EBV-CTLs, since these express low levels of the TARC receptor, CCR4. We hypothesized that forced expression of CCR4 by redirected EBV-CTLs would improve their homing to the EBV−/CD30+ HD cells. The full length of CCR4 receptor was cloned into the SFG retroviral vector and used to transduce both activated T cells and EBV-CTLs obtained from 6 and 4 healthy donors, respectively. Expression of CCR4 was 12±8% on activated T cells (mainly on CD4+ cells, 12±6%) and 4±5% on EBV-CTLs. After transduction with a CCR4, but not a control vector, expression of CCR4 increased to 53±24% (CD4+ 27±15% and CD8+ 17±9%) on activated T cells and 30±19% on EBV-CTLs. We then evaluated the capacity of control and transgenic T cells and EBV-CTLs to migrate in response to TARC, using a trans-well migration assay. Migration was tested against different CD30+ tumor lines producing TARC at low (Karpas wild type, <32 pg/ml) or high levels (Karpas engineered to produce TARC, HDLM-2 and L428, all TARC >2000pg/mL), measured by ELISA. The percent of cells migrating in the trans-well assay was significantly increased for CCR4 transgenic CD8+ selected T cells (54±11% with Karpas/TARC vs. 8±2% with media vs. 8±4% with Karpas-wt). Migration of control OKT3/28 blasts was less than 15% in all the conditions. Migration was significantly inhibited by the addition of antibody blocking TARC (<10%). An improved migration of CCR4+ CD8+ cells was observed also towards HDLM-2 (48±7%) and L428 (45±16%) as compared to control T cells (21±7% and 23±7%, respectively). Similarly, CCR4+ EBV-CTL showed improved migration towards Karpas/TARC (26±14%) as compared to Karpas/wt (12±8%) or media (10±7%). This genetic modification did not modify either the phenotype or the antigen specificity of EBV-CTLs, which retained the capacity to kill autologous EBV+ lymphoblastoid cells. We then determined if forced expression of CCR4 receptor was functional in vivo. To track homing of transgenic T cells, we transduced them with the FireFlyluciferase (FFLuc) vector and followed signal with a bioluminescent system (IVIS, Xenogen). Sublethally irradiated SCID mice were implanted s.c. with Karpas/wt on the left side and Karpas/TARC on the right side. When tumors were measurable, FFLuc+CCR4+ T cells were injected iv. By 24 hours post injection, signal was detectable only at the side of TARC secreting tumor cells, and signal persisted at 10 to 16 fold higher levels on the TARC+ side for >7 days. These data suggest that the migration of CARCD30 EBV-CTL to EBV−/CD30+ HD can be augmented by co-expressing the CCR4 receptor.

Download Full-text

Cytotoxic CD8 T Cell Immune Responses to Wilms Tumor Protein (WT-1) Characterizes Immunosuppression-Responsive Myelodysplasia (MDS).

Blood ◽

10.1182/blood.v108.11.849.849 ◽

2006 ◽

Vol 108 (11) ◽

pp. 849-849 ◽

Cited By ~ 2

Author(s):

Elaine M. Sloand ◽

Katayoun Rezvani ◽

Agnes Yong ◽

Daniel Douek ◽

Roger Kurlander ◽

...

Keyword(s):

Bone Marrow ◽

T Cells ◽

T Cell ◽

Cytotoxic Activity ◽

Cyclin D1 ◽

Wilms Tumor ◽

Cytotoxic T Cells ◽

Cd8 T Cell ◽

Trisomy 8 ◽

Cd8 Cells

Abstract Clinical observations and experimental evidence link bone marrow failure in myelodysplastic syndrome (MDS) with a T cell-dominated immunologically-mediated pathophysiology in some patients. Indeed, among 129 patients treated with immunosuppression at NIH, trisomy 8 was associated with hematologic response to immunosuppression. We have demonstrated that trisomy 8 patients have oligoclonal CD8 T cell expansion, as determined by increased proportions of one or more T cell receptor (TCR) V beta subfamilies (Sloand et al. Blood106:841; 2005) which had cytotoxic activity toward trisomy 8 cell progenitors. Here we examine the response of cytotoxic T cells to cyclin D1 and Wilms tumor protein (WT-1); these candidate autoantigens had earlier been observed to be over-expressed in trisomy 8 CD34 cell in our microarray analysis (Chen et al. Blood 104:4210, 2004 ). Bone marrow mononuclear cells from 19 trisomy 8 patients (defined by cytogenetics and FISH) had significantly increased levels of WT-1 mRNA and protein expression compared to normal CD34 cells by real time PCR and immunoblot, respectively (p<0.001). When patient and control CD8 cells were cultured in the presence of WT-1- and cyclin D1-loaded HLA-A2-restricted antigen-presenting cells (using three different HLA-A0201- restricted epitopes of WT-1 and four different epitopes for CD1), eight patients’ CD8 cell tested positive for interferon gamma, indicating a cytotoxic response. Staining with labeled MHC class I A2-restricted tetramers used to measure WT-1-specific cells showed concordant results in all eight patients. Tetramer staining was increased in 12 of 14 trisomy 8 patients examined. Cytotoxic T cells specific for WT-1 were present within the expanded V β subfamilies previously found to suppress trisomy 8 cell proliferation in vitro. CD8 cells from another eight MDS patients without trisomy 8 but who had responded to immunosuppression, sampled prior to treatment, also demonstrated WT1-specific cytotoxic activity, but only two of 18 non-responders showed measurable levels of WT-1-specific cytotoxic T cells (entire treated cohort seen in Fig 1). We infer from these data an autoimmune pathophysiology for trisomy 8 MDS with: 1) over-expression of WT-1 by the aneuploid clone; 2) a specific cytotoxic CD8 T cell immune response to WT-1; 3) subsequent cytotoxic T cell marrow suppression by apoptosis, either by cross reactivity or a bystander effect; and 4) improvement in hematopoiesis after immunosuppression. Other MDS which is responsive to immunosuppression may also be mediated by WT1. Figure Figure

Download Full-text

Capillary blood as an alternative specimen for enumeration of percentages of lymphocyte subsets

BMC Research Notes ◽

10.1186/s13104-019-4659-4 ◽

2019 ◽

Vol 12 (1) ◽

Cited By ~ 2

Author(s):

Supanart Srisala ◽

Nutkridta Pongsakul ◽

Thiantip Sahakijpicharn ◽

Suradej Hongeng ◽

Somchai Chutipongtanate ◽

...

Keyword(s):

T Cells ◽

Lymphocyte Count ◽

Lymphocyte Subsets ◽

Point Of Care ◽

Cytotoxic T Cells ◽

Venous Blood ◽

Total Lymphocyte Count ◽

Capillary Blood ◽

Cd8 Cells ◽

Total Lymphocyte

Abstract Objective Capillary blood has been increasingly used in point-of-care setting for clinical monitoring in immunology and infectious diseases. We explored whether percentages of lymphocyte subsets (T-cells; CD3+, helper T-cells; CD4+, cytotoxic T-cells; CD8+, B-cells; CD19+, NK cells; CD56+, gamma delta T-cells, and regulatory T-cells) with regard to total lymphocyte count from capillary and venous blood of healthy volunteers were in good agreement. Results All percentages of lymphocyte subsets with regard to total lymphocyte count from capillary blood were significantly correlated with those from venous blood (r ≥ 0.9 for every cell type). However, Bland–Altman plots showed high agreement between capillary and venous samples only in those of CD3+, CD4+, and CD8+ cells (limit of agreement percentages from mean venous blood < 20%). However, the agreement of percentages of other lymphocyte subsets from venous and capillary blood was mediocre. We concluded that capillary blood could be used as an alternative for venous blood to determine percentages of CD3+, CD4+, and CD8+ cells with regard to total lymphocyte count.

Download Full-text

Donor CD8 cells prevent allogeneic marrow graft rejection in mice: potential implications for marrow transplantation in humans.

Journal of Experimental Medicine ◽

10.1084/jem.178.2.703 ◽

1993 ◽

Vol 178 (2) ◽

pp. 703-712 ◽

Cited By ~ 135

Author(s):

P J Martin

Keyword(s):

T Cells ◽

Mhc Class I ◽

Mhc Class Ii ◽

Cytotoxic T Cells ◽

Class I ◽

Cd4 Cells ◽

Cd8 Cells ◽

Donor Cells ◽

Donor T Cells ◽

Allogeneic Marrow

Numerous experimental models have demonstrated that graft-vs.-host disease (GVHD) does not occur in irradiation chimeras when the graft does not contain mature, immunocompetent T lymphocytes, but clinical studies have shown that T cell depletion of donor marrow can be associated with a greatly increased risk of graft failure. We have developed a model where engraftment of (C57BL/6J x C3H/HeJ)F1 (B6C3) marrow in 800-cGy-irradiated (BALB/cJ x C57BL/6J)F1 (CB6) recipients depends on the presence of donor T cells in the graft. Recipients transplanted with 5.0 x 10(6) marrow cells depleted of T lymphocytes showed host lymphoid and myeloid reconstitution, whereas recipients transplanted with the same marrow plus 2.5 x 10(5) purified donor T cells showed donor reconstitution. Adding as few as 0.5 x 10(5) CD8-enriched donor T cells to marrow grafts containing 5.0 x 10(6) T cell-depleted donor cells was sufficient to enable donor reconstitution, while surviving recipients transplanted with the same marrow and 0.5-2.5 x 10(5) CD4-enriched donor cells showed only host reconstitution. To address the question of whether donor CD4 cells could facilitate engraftment under conditions where GVHD would not represent a limiting factor, engraftment of bm1 marrow was tested in major histocompatibility complex (MHC) class I-disparate B6.Ly5a recipients. Results indicated that the donor CD8-enriched population was at least fivefold more active than the CD4-enriched population for facilitating allogeneic marrow engraftment in this strain combination. Thus, the lymphokines and MHC class II-specific cytotoxic T cells generated by CD4 cells were relatively ineffective for enhancing engraftment, possibly reflecting the fact that the host T cells that contain effectors responsible for causing rejection do not express MHC class II antigens. The ability of donor CD8 cells to facilitate engraftment could reflect the activity of a cytokine uniquely elaborated after recognition of an MHC class I disparity. More likely, the graft-enhancing effect of donor CD8 cells may result from the generation of MHC class I-specific or class I-restricted cytotoxic T cells that recognize the host CD4 and CD8 cells responsible for causing rejection. The possibility remains that other mechanisms such as veto inactivation of host T cells by donor CD8 cells may also contribute to the graft-enhancing effect.

Download Full-text