Thymus Degeneration and Regeneration

The immune system’s ability to resist the invasion of foreign pathogens and the tolerance to self-antigens are primarily centered on the efficient functions of the various subsets of T lymphocytes. As the primary organ of thymopoiesis, the thymus performs a crucial role in generating a self-tolerant but diverse repertoire of T cell receptors and peripheral T cell pool, with the capacity to recognize a wide variety of antigens and for the surveillance of malignancies. However, cells in the thymus are fragile and sensitive to changes in the external environment and acute insults such as infections, chemo- and radiation-therapy, resulting in thymic injury and degeneration. Though the thymus has the capacity to self-regenerate, it is often insufficient to reconstitute an intact thymic function. Thymic dysfunction leads to an increased risk of opportunistic infections, tumor relapse, autoimmunity, and adverse clinical outcome. Thus, exploiting the mechanism of thymic regeneration would provide new therapeutic options for these settings. This review summarizes the thymus’s development, factors causing thymic injury, and the strategies for improving thymus regeneration.

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Early Recovery of Thymus-Derived Naïve T Cells in Pediatric Patients (pts) Treated with Non-Myeloablative Allogeneic Peripheral Blood Stem Cell Transplantation (NMSCT) for Cancer.

Blood ◽

10.1182/blood.v108.11.310.310 ◽

2006 ◽

Vol 108 (11) ◽

pp. 310-310

Author(s):

Terry J. Fry ◽

Alison R. Rager ◽

Frances Hakim ◽

Cynthia Love ◽

Paula Layton ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

High Risk ◽

Peripheral Blood ◽

T Cell Subsets ◽

Immune Recovery ◽

Early Recovery ◽

Thymic Function ◽

Cell Counts ◽

Increased Risk

Abstract Background: Current SCT approaches consistently achieve rapid donor myeloid engraftment, but delayed immune recovery remains a significant obstacle and results in increased risk of infection and relapse. T cells are regenerated via 2 pathways, thymus-derived and peripheral expansion, processes for which IL-7 is critical. We postulated that non-myeloablative pre-transplant conditioning might preserve thymic function in pediatric SCT recipients thus enhancing thymus-derived naïve T cell regeneration. Methods: We analyzed T cell subsets, T cell receptor excision circles (TREC), and IL-7 levels in peripheral blood after SCT in 21 pediatric pts with high-risk malignancies (median age 14, range 4–21). Fludarabine-based induction chemotherapy was administered for disease control and targeted CD4 count reduction. Pre-transplant conditioning consisted of cyclophosphamide (1,200 mg/m2/day) and fludarabine (30 mg/m2/day) × 4 days plus melphalan (100 mg/m2 × 1 dose in sarcoma pts). Grafts consisted of G-CSF mobilized unmodified peripheral blood stem cells from 5–6/6 HLA-matched first-degree relatives (median CD34 dose 11.7 × 10E6/kg, range 4.4–19.1; median CD3 dose 416 × 10E6/kg, range 228–815). Cyclosporine was used for GVHD prophylaxis. Results: Donor-derived engraftment was rapid (absolute neutrophil count > 500/uL median day 9, range 8–11). Complete donor lymphoid chimerism (>95% by VNTR-PCR on CD3 sorted peripheral blood) was achieved in all by day 28. Immune recovery was brisk and sustained. Substantial numbers of naïve (CD45RA+/CD62L+) CD4+ and CD8+ T-cells were detected at day 28 (Fig 1). There was a steady increase in TREC from 3 to 12 months consistent with early, robust thymic-dependant T cell generation (Fig 2). This was not seen in adult pts treated on a parallel trial (data not shown). IL-7 levels were elevated and inversely correlated with T cell counts (r=−0.56, p<0.0001). Conclusions: Targeted immune depletion and NMSCT results in rapid, sustained immune reconstitution in pediatric pts with malignancy. Preserved thymic function appears to contribute to naïve T cell recovery in this setting. We postulate that non-myeloablative conditioning is thymus sparing and that this, in combination with immune depletion-induced IL-7 elevation, promotes early thymic-derived lymphoid recovery. This approach may serve as a strategy to overcome the prolonged immunodeficiency commonly encountered after allogeneic SCT in pediatrics and might be used as a platform to direct allogeneic anti-tumor immune responses in high-risk childhood cancers. Figure 1 Figure 1. Figure 2 Figure 2.

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Comparison of Immune Reconstitution After Unrelated and Related T-Cell–Depleted Bone Marrow Transplantation: Effect of Patient Age and Donor Leukocyte Infusions

Blood ◽

10.1182/blood.v93.2.467.402k22_467_480 ◽

1999 ◽

Vol 93 (2) ◽

pp. 467-480 ◽

Cited By ~ 18

Author(s):

T.N. Small ◽

E.B. Papadopoulos ◽

F. Boulad ◽

P. Black ◽

H. Castro-Malaspina ◽

...

Keyword(s):

Bone Marrow ◽

Bone Marrow Transplantation ◽

T Cell ◽

Marrow Transplantation ◽

Immune Reconstitution ◽

Opportunistic Infections ◽

Cd8 T Cell ◽

Cell Populations ◽

Increased Risk ◽

Life Threatening

Unrelated bone marrow transplantation (BMT) is often complicated by fatal opportunistic infections. To evaluate features unique to immune reconstitution after unrelated BMT, the lymphoid phenotype, in vitro function, and life-threatening opportunistic infections after unrelated and related T-cell–depleted (TCD) BMT were analyzed longitudinally and compared. The effects of posttransplant donor leukocyte infusions to treat or prevent cytomegalovirus (CMV) or Epstein-Barr virus (EBV) infections on immune reconstitution were also analyzed. This study demonstrates that adult recipients of TCD unrelated BMTs experience prolonged and profound deficiencies of CD3+, CD4+, and CD8+ T-cell populations when compared with pediatric recipients of unrelated BMT and adults after related BMT (P < .01), that these adults have a significantly increased risk of life-threatening opportunistic infections, and that the rate of recovery of CD4 T cells correlates with the risk of developing these infections. Recovery of normal numbers of CD3+, CD8+, and CD4+ T-cell populations is similar in children after related or unrelated BMT. This study also demonstrates that adoptive immunotherapy with small numbers of unirradiated donor leukocytes can be associated with rapid restoration of CD3+, CD4+, and CD8+T-cell numbers, antigen-specific T-cell responses, and resolution of CMV- and EBV-associated disease after unrelated TCD BMT.

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Nutritional imbalances and infections affect the thymus: consequences on T-cell-mediated immune responses

Proceedings of The Nutrition Society ◽

10.1017/s0029665110002545 ◽

2010 ◽

Vol 69 (4) ◽

pp. 636-643 ◽

Cited By ~ 58

Author(s):

Wilson Savino ◽

Mireille Dardenne

Keyword(s):

T Cell ◽

Infectious Diseases ◽

Opportunistic Infections ◽

Cell Subset ◽

Extracellular Proteins ◽

Thymic Epithelial Cells ◽

Zn Deficiency ◽

Elderly Persons ◽

Thymic Atrophy ◽

Increased Risk

The thymus gland, where T lymphocyte development occurs, is targeted in malnutrition secondary to protein energy deficiency. There is a severe thymic atrophy, resulting from massive thymocyte apoptosis (particularly affecting the immature CD4+CD8+cell subset) and decrease in cell proliferation. The thymic microenvironment (the non-lymphoid compartment that drives intrathymic T-cell development) is also affected in malnutrition: morphological changes in thymic epithelial cells were found, together with a decrease of thymic hormone production, as well as an increase of intrathymic contents of extracellular proteins. Profound changes in the thymus can also be seen in deficiencies of vitamins and trace elements. Taking Zn deficiency as an example, there is a substantial thymic atrophy. Importantly, marginal Zn deficiency in AIDS subjects, children with diarrhoea and elderly persons, significantly impairs the host's immunity, resulting in an increased risk of opportunistic infections and mortality; effects that are reversed by Zn supplementation. Thymic changes also occur in acute infectious diseases, including a severe thymic atrophy, mainly due to the depletion of CD4+CD8+thymocytes, decrease in thymocyte proliferation, in parallel to densification of the epithelial network and increase in the extracellular matrix contents, with consequent disturbances in thymocyte migration and export. In conclusion, the thymus is targeted in several conditions of malnutrition as well as in acute infections. These changes are related to the impaired peripheral immune response seen in malnourished and infected individuals. Thus, strategies inducing thymus replenishment should be considered as adjuvant therapeutics to improve immunity in malnutrition and/or acute infectious diseases.

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Comparison of Immune Reconstitution After Unrelated and Related T-Cell–Depleted Bone Marrow Transplantation: Effect of Patient Age and Donor Leukocyte Infusions

Blood ◽

10.1182/blood.v93.2.467 ◽

1999 ◽

Vol 93 (2) ◽

pp. 467-480 ◽

Cited By ~ 358

Author(s):

T.N. Small ◽

E.B. Papadopoulos ◽

F. Boulad ◽

P. Black ◽

H. Castro-Malaspina ◽

...

Keyword(s):

Bone Marrow ◽

Bone Marrow Transplantation ◽

T Cell ◽

Marrow Transplantation ◽

Immune Reconstitution ◽

Opportunistic Infections ◽

Cd8 T Cell ◽

Cell Populations ◽

Increased Risk ◽

Life Threatening

Abstract Unrelated bone marrow transplantation (BMT) is often complicated by fatal opportunistic infections. To evaluate features unique to immune reconstitution after unrelated BMT, the lymphoid phenotype, in vitro function, and life-threatening opportunistic infections after unrelated and related T-cell–depleted (TCD) BMT were analyzed longitudinally and compared. The effects of posttransplant donor leukocyte infusions to treat or prevent cytomegalovirus (CMV) or Epstein-Barr virus (EBV) infections on immune reconstitution were also analyzed. This study demonstrates that adult recipients of TCD unrelated BMTs experience prolonged and profound deficiencies of CD3+, CD4+, and CD8+ T-cell populations when compared with pediatric recipients of unrelated BMT and adults after related BMT (P < .01), that these adults have a significantly increased risk of life-threatening opportunistic infections, and that the rate of recovery of CD4 T cells correlates with the risk of developing these infections. Recovery of normal numbers of CD3+, CD8+, and CD4+ T-cell populations is similar in children after related or unrelated BMT. This study also demonstrates that adoptive immunotherapy with small numbers of unirradiated donor leukocytes can be associated with rapid restoration of CD3+, CD4+, and CD8+T-cell numbers, antigen-specific T-cell responses, and resolution of CMV- and EBV-associated disease after unrelated TCD BMT.

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A case of Good’s syndrome complicated by erythema multiforme

BMJ Case Reports ◽

10.1136/bcr-2019-229999 ◽

2019 ◽

Vol 12 (8) ◽

pp. e229999

Author(s):

Laura R Glick ◽

William Wyatt Wilson ◽

Michelle Fletcher

Keyword(s):

T Cell ◽

B Cell ◽

Erythema Multiforme ◽

Opportunistic Infections ◽

Case Reports ◽

Skin Lesions ◽

Anterior Mediastinal Mass ◽

Good’S Syndrome ◽

Increased Risk ◽

Simplex Virus

Good’s syndrome (GS) is a rare, adult-onset combined B cell and T cell immunodeficiency with an associated thymoma. These patients have an increased risk of bacterial, fungal, viral and opportunistic infections. This report describes a 75-year-old female patient who presented with a full body rash and an anterior mediastinal mass. She underwent a biopsy of her rash and mass, which revealed erythema multiforme and WHO Type A thymoma, respectively. During her hospitalisation, she was also found to have oropharyngeal candidiasis, methicillin-susceptible Staphylococcus aureus bacteraemia and herpes simplex virus type 2 (HSV-2) skin lesions. Based on the number of infections and severity of her rash, an immunocompromised state was suspected. Immunological testing revealed a B cell and T cell deficiency as well as low serum immunoglobulins. This combination of hypogammaglobulinaemia and thymoma led to a diagnosis of GS. While there have been many case reports of GS, this is the first report of the immunodeficiency presenting with erythema multiforme.

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Autoimmune Lymphoproliferative Syndrome

Journal of Medical Biochemistry ◽

10.2478/v10011-010-0006-y ◽

2010 ◽

Vol 29 (1) ◽

pp. 15-18 ◽

Cited By ~ 1

Author(s):

Manole Cojocaru ◽

Inimioara Cojocaru ◽

Isabela Silosi ◽

Camelia Vrabie

Keyword(s):

T Cell ◽

T Cell Receptors ◽

Surface Markers ◽

Autoimmune Lymphoproliferative Syndrome ◽

Lymphocyte Apoptosis ◽

Cd8 Cells ◽

Increased Risk ◽

Abnormal Lymphocyte ◽

Lymphoproliferative Syndrome ◽

Alpha Beta

Autoimmune Lymphoproliferative SyndromeThe autoimmune lymphoproliferative syndrome (ALPS) is a rare disease. ALPS is an inherited condition that affects both sexes. ALPS is not cancer, it is not infectious, and its incidence has not yet been estimated. ALPS generally does not lead to death and most individuals with ALPS are able to live normal lives. ALPS is a disorder associated with abnormal lymphocyte apoptosis, lymphoproliferation, and autoimmunity. Serologic testing is critical in the evaluation of these individuals. Lymphoproliferation in ALPS patients is generally benign, but they are at increased risk for the development of Hodgkin's and non-Hodgkin's lymphoma. It is characterized by massive lymphoadenopathy, splenomegaly, autoimmunity including episodes of immune hemolityc anemia, thrombocytopenia, and neutropenia. ALPS patients have lymphocytosis and a number of lymphocyte abnormalities, including the marked expansion of T lymphocytes that express alpha/beta T-cell receptors, but neither CD4 nor CD8 surface markers (TCR alpha/beta+; CD4-; CD8- cells).

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