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Terry J Fry

Publications and source records attributed to Terry J Fry.

15 recordsLinked to original sources
PubMed2026

Reduced CCL/Be-specific CD4+ T cells in CCL3-deficient or peptide-MHCII CAR-T cell-treated mice.

In chronic beryllium disease (CBD), elevated levels of the inflammatory chemokines CCL3 and CCL4 in the lungs coincide with expanded populations of CD4+ T cells specific to beryllium-modified (Be-modified) peptides derived from these chemokines. Here, we generated HLA-DP2 transgenic (Tg) CCL3-deficient mice (CCL3-/-) that also lack CCL4 to investigate their role in disease development. Be-exposed CCL3-/- mice maintained normal numbers of lung macrophages and dendritic cells (DCs) but exhibited significantly reduced total and HLA-DP2-CCL/Be tetramer-specific CD4+ T cells, IFN-γ-producing CD4+ T cells, and peribronchovascular aggregates, consistent with attenuated inflammation. CCL3 was predominantly expressed in macrophages and DCs, and bone marrow chimera studies confirm that hematopoietic-derived DCs are the key regulators of CCL/Be-specific CD4+ T cell responses. RNA-seq of lung-resident CCL4/Be tetramer+ CD4+ T cells revealed a transcriptional profile enriched for inflammatory and cholesterol-metabolism pathways, with elevated expression of Ifng, Tnf, and Il17a. Moreover, Be-exposed HLA-DP2 Tg mice lacking TNF-α or treated with peptide-MHCII CAR-T cells targeting CCL4/Be-specific CD4+ T cells showed reduced T cell responses and cellular aggregates. These findings demonstrate that CCL3 and CCL4 promote CCL/Be-specific CD4+ T cell responses and highlight peptide-MHCII CAR-T cells as a potentially novel strategy for depleting self-peptide/Be-specific CD4+ T cells in CBD.

Animals↗
PubMed2006

Autoimmunity during lymphopenia: a two-hit model.

The immune system has evolved elaborate mechanisms to respond to diverse antigens while minimizing the risk for autoimmune reactivity. During lymphopenia, however, some mechanisms that normally serve to maintain host tolerance are temporarily suspended. Peripheral T cells proliferate in response to self-antigens in lymphopenic hosts, but proliferation toward these same antigens is prevented when T cell numbers are normal. This process, termed homeostatic peripheral expansion, augments peripheral T cell number and limits repertoire skewing during recovery from lymphopenia and also predisposes lymphopenic hosts to autoimmune disease. This paper reviews murine and human settings in which autoimmunity occurs in the context of lymphopenia. We propose a two-hit model, in which lymphopenia plus another insult is sufficient to induce autoimmune disease. Among the secondary insults that appear sufficient to induce autoimmunity during lymphopenia are overproduction of IL-21 as occurs in the NOD.SCID mouse, depletion of Tregs as demonstrated in murine colitis and gastritis models, and tissue inflammation as seen in HIV infected patients who develop immune reconstitution inflammatory syndrome (IRIS). Delineating critical cofactors which result in autoimmune disease during lymphopenia can provide insight into the pathophysiology of naturally occurring autoimmune diseases as well as generating testable hypothesis for inducing tumor-specific autoimmunity in lymphopenic hosts with cancer.

Animals↗
PubMed2006

IL-7 in allogeneic transplant: clinical promise and potential pitfalls.

Much progress has been made in the field of allogeneic stem cell transplantation. However, one major barrier is the delay in immune recovery that can persist for months post-transplant and results in increased susceptibility to infection and relapse of malignancy. Strategies to improve immune recovery must be balanced with the potential for those therapies to exacerbate graft vs host disease. Interleukin 7 is a member of the gammac cytokine family that is required for T-cell development and maintenance of naïve T-cell populations. In addition, IL-7 plays a major role in the expansion of mature T-cells that occurs during lymphopenia and therapeutic IL-7 can enhance both quantitative and functional immune recovery following T-cell depletion. Thus, this agent holds much promise as an immunorestorative agent and as an adjuvant to vaccines or adoptive immunotherapy. Clinic trials with IL-7 are underway. Murine studies with IL-7 in the allogeneic transplant have demonstrated that the potent immune effects of this agent can also be achieved in this setting. However, these studies have indicated that the potential for IL-7 to worsen GVHD exists and that this effect may abrogate the immune benefits. Thus, careful consideration of how best to incorporate IL-7 into allogeneic trials will be needed if the full potential of this agent is to be realized.

Animals↗
PubMed2005

The many faces of IL-7: from lymphopoiesis to peripheral T cell maintenance.

IL-7 is well known as a lymphopoietic cytokine, but recent studies have also identified a critical role for IL-7 in peripheral T cell homeostasis. IL-7 is well poised to serve as a homeostatic cytokine because it is produced by resting stromal cells, the IL-7R is present on most T cells, and IL-7 down-regulates its own receptor. These features allow IL-7 to signal large numbers of resting T cells and to be efficiently used when supplies are limiting. Consistent with this, in normal hosts, IL-7 is required for survival of naive T cell populations, and IL-7 contributes to homeostatic cycling of naive and memory cells. In addition, lymphopenic hosts accumulate increased levels of IL-7, and the supranormal levels are largely responsible for inducing homeostatic peripheral expansion in response to lymphopenia. Thus, IL-7 plays critical and nonredundant roles in both T cell lymphopoiesis and in maintaining and restoring peripheral T cell homeostasis.

Animals↗
PubMed2005

Adjuvant IL-7 or IL-15 overcomes immunodominance and improves survival of the CD8+ memory cell pool.

Current models of T cell memory implicate a critical role for IL-7 in the effector-to-memory transition, raising the possibility that IL-7 therapy might enhance vaccine responses. IL-7 has not been studied, to our knowledge, before now for adjuvant activity. We administered recombinant human IL-7 (rhIL-7) to mice during immunization against the male antigen HY and compared these results with those obtained from mice immunized with rhIL-2 and rhIL-15. Administration of rhIL-7 or rhIL-15, but not rhIL-2, increased effector cells directed against these dominant antigens and dramatically enhanced CD8(+) effectors to subdominant antigens. The mechanisms by which the cytokines augmented effector pool generation were multifactorial and included rhIL-7-mediated costimulation and rhIL-15-mediated augmentation of the proliferative burst. The contraction phase of the antigen-specific response was exaggerated in cytokine-treated mice; however, CD8(+) memory pools in rhIL-7- or rhIL-15-treated groups demonstrated superior long-term survival resulting in quantitative advantages that remained long after the cytokines were discontinued, as demonstrated by improved survival after challenge with an HY-expressing tumor undertaken several weeks after cytokine cessation. These results confirm the adjuvant activity of rhIL-15 and demonstrate that rhIL-7 also serves as a potent vaccine adjuvant that broadens immunity by augmenting responses to subdominant antigens and improving the survival of the CD8(+) T cell memory pool.

Adjuvants, Immunologic↗
PubMed2004

Flt3 ligand enhances thymic-dependent and thymic-independent immune reconstitution.

Despite recent progress in our understanding of the biology of T-cell homeostasis, clinically available therapies to substantially improve immune reconstitution in patients sustaining T-cell depletion are lacking. T cells are regenerated via a dynamic interplay between thymopoiesis and thymic-independent homeostatic peripheral expansion (HPE). Using athymic mice subjected to T-cell depletion, we observed that HPE is critically dependent on dendritic cells (DCs) for presentation of antigen, raising the possibility that the availability of DCs might be limiting in vivo for HPE to occur efficiently. Indeed, flt3 ligand (flt3L) treatment of athymic mice subjected to T-cell depletion (without DC depletion) substantially enhanced HPE and improved immune competence. Following bone marrow transplantation (BMT) in athymic hosts, both dendritic cells and T cells were profoundly depleted and flt3L therapy restored DC numbers and enhanced HPE. In addition, thymus-bearing BMT recipients treated with flt3L regenerated increased numbers of thymic-dependent progeny with increased numbers of T-cell receptor excision circle (TREC)-positive T cells, indicating increased thymopoiesis. Therefore, flt3L is a potent immunorestorative agent that enhances both thymic-dependent and thymic-independent pathways of T-cell regeneration.

Animals↗
PubMed2002

IL-7 therapy dramatically alters peripheral T-cell homeostasis in normal and SIV-infected nonhuman primates.

Interleukin-7 (IL-7) is important for thymopoiesis in mice and humans because IL-7 receptor alpha (IL-7Ralpha) mutations result in a severe combined immunodeficiency phenotype with severe thymic hypoplasia. Recent evidence has indicated that IL-7 also plays an important role as a regulator of T-cell homeostasis. Here we report the immunologic effects of recombinant human IL-7 (rhIL-7) therapy in normal and simian immunodeficiency virus (SIV)-infected nonhuman primates. Cynomolgus monkeys receiving 10 days of rhIL-7 showed substantial, reversible increases in T-cell numbers involving a dramatic expansion of both naive and nonnaive phenotype CD4(+) and CD8(+) subsets. Although IL-7 is known to have thymopoietic effects in mice, we observed marked declines in the frequency and absolute number of T-cell receptor excision circle-positive (TREC(+)) cells in the peripheral blood and dramatic increases in the percentage of cycling T cells in the peripheral blood as measured by Ki-67 expression (baseline less than 5% to approximately 50% after 6 days of therapy) and ex vivo bromodeoxyuridine (BrdU) incorporation. Similarly, moderately CD4- depleted SIV-infected macaques treated with rhIL-7 also had significant increases in peripheral blood CD4(+) and CD8(+) T cells following rhIL-7 therapy. Thus, rhIL-7 induces dramatic alterations in peripheral T-cell homeostasis in both T-cell-replete and T-cell-depleted nonhuman primates. These results further implicate IL-7 as a promising immunorestorative agent but illustrate that a major component of its immunorestorative capacity reflects effects on mature cells. These results also raise the possibility that IL-7 therapy could be used to temporarily modulate T-cell cycling in vivo in the context of immunotherapies such as vaccination.

Animals↗
PubMed2002

Interleukin 7 worsens graft-versus-host disease.

Impaired immune reconstitution has moved to the forefront of clinical problems limiting progress in allogeneic bone marrow transplantation (BMT). The identification of therapies that can enhance immune reconstitution by increasing thymopoiesis is critical to solving this problem. Interleukin 7 (IL-7) is the most potent thymopoietic cytokine identified thus far. To study the effects of IL-7 on immune reconstitution and graft-versus-host disease (GVHD) following allogeneic BMT, we administered recombinant human IL-7 (rhIL-7) in a murine parent into an F1 model. Results showed that rhIL-7 therapy lowered the "threshold" T-cell dose required to induce both clinical signs of GVHD as well as lethal GVHD. Histologic analysis of GVHD target tissues revealed that rhIL-7 increased the degree of inflammation and tissue damage observed at all T-cell doses studied, but did not change the pattern of organs affected or the histologic appearance of the GVHD within target organs. In addition, we evaluated the capacity for rhIL-7 to enhance thymopoiesis in the setting of allogeneic T cell-depleted (TCD) and T-cell-replete BMT. We observed that rhIL-7 therapy enhanced thymic function in TCD allogeneic BM transplant recipients, but not in animals that received even modest doses of T cells presumably due to thymic toxicity of the graft-versus-host reaction. Thus, caution must be exercised as IL-7 is developed clinically as an immunorestorative agent for use in the setting of allogeneic BMT. These results suggest that use of IL-7 should be limited to the setting of TCD BMT to obtain the greatest benefit on immune competence with the least toxicity.

Animals↗
PubMed2002

Bax deficiency partially corrects interleukin-7 receptor alpha deficiency.

The requirement for cytokines in hematopoiesis is partly attributable to the protection of cells from apoptosis. Since IL-7 is required for normal T cell development, we evaluated the role of Bax in vivo by generating mice deficient in both Bax and the IL-7 receptor alpha chain (IL-7R). Starting at birth, we observed complete recovery of all stages of alphabeta thymocyte development up to 4 weeks of age. However, by 12 weeks of age, thymic cellularity had reverted to that of mice deficient in IL-7R alone. The BH3 only proteins, Bad and Bim, were also part of the death pathway repressed by IL-7. Thus, in young mice, Bax emerges as an essential protein in the death pathway induced by IL-7 deficiency.

Aging↗
PubMed2002

Interleukin-7 and immunorestoration in HIV: beyond the thymus.

One of the hallmarks of untreated HIV infection is a progressive loss of effective immunity to both HIV-associated and non-HIV antigens. Combination antiretroviral therapy can frequently control viral replication, resulting in variable levels of immune reconstitution, but has not resulted in restoration of effective immunity to the virus. Understanding the limitations of immune reconstitution following highly active antiretroviral therapy (HAART) and identifying approaches to enhance immunity in this context may not only improve outcome for patients with HIV infection but could also provide insight for immune reconstitution in other conditions associated with T cell depletion.

Anti-HIV Agents↗
PubMedDate not supplied

Escape from immune surveillance does not result in tolerance to tumor-associated antigens.

Despite expression of tumor-associated or tumor-specific antigens by most tumors, evasion of protective T-cell immunity is the rule rather than the exception. Understanding whether tumor immune escape primarily represents T-cell neglect, anergy/tolerance, or quantitative limits of an existent immune response is central to developing new strategies to enhance antitumor immunity. The authors studied the immune response to MB49, a tumor that naturally expresses HY. Immune surveillance was effective following low-dose tumor inocula, since normal female mice showed a diminished incidence and slower growth rate of MB49 compared with T-cell-depleted female mice and male mice. Following high-dose tumor inoculation, females developed large, progressive tumors but continued to demonstrate immune responses to class I and class II restricted HY epitopes. The HY reactive T cells remained capable of executing HY immune responses since T cells adoptively transferred from MB49-bearing animals mediated accelerated HY skin graft rejection compared with those taken from naive mice. Thus, MB49 does not induce immune tolerance to HY but rather escapes immune surveillance largely due to quantitative limits of the immune response. Treatment of tumor-bearing animals with rhIL7 significantly increased the number of T cells responding to HY but did not alter tumor growth rate. These results demonstrate that escape from immune surveillance does not necessarily imply immune tolerance to tumor antigens and that immunotherapy need not overcome tumor-induced tolerance per se, and suggest that substantial opportunities remain in tumor-bearing hosts to amplify weak but persistent antitumor immune responses.

Adoptive Transfer↗
PubMedDate not supplied

Cytokine signals in T-cell homeostasis.

Thymic production of T cells declines rapidly with age, and therefore homeostatic cycling (HC) of mature lymphocytes plays an important role in maintaining stable numbers of mature T lymphocytes bearing sufficient repertoire diversity. Following lymphocyte depletion, HC changes in quality and magnitude, resulting in homeostatic peripheral expansion (HPE), a state of widespread T-cell cycling that serves to increase T-cell number and to maintain T-cell repertoire diversity to the greatest extent possible. Recent studies delineating the requirements for HC and HPE have shown that naive CD4+ cells and naive CD8+ cells require both IL7 and TCR engagement for survival, cycling, and homeostatic expansion, whereas CD8+ memory cells are maintained and expanded by cytokine signals alone, independent of TCR engagement. While basal levels of IL15 are sufficient for HC and HPE of CD8+ memory cells, supranormal levels of IL7 will also suffice. The requirements for memory CD4+ cells remain unclear, but current models hypothesize that either IL7 or TCR triggering may be sufficient. Thus, the changes in immune physiology that are present in lymphopenic hosts can be largely accounted for by cytokine-driven signals, especially those rendered by IL7 or IL15. As the alterations in immune physiology present in lymphopenic hosts may be conducive to stronger antitumor immune responsiveness, careful delineation of the factors responsible may be expected to give rise to approaches to augment the effectiveness of current antitumor immunotherapies.

Animals↗
PubMedDate not supplied

IL-7 administration to humans leads to expansion of CD8+ and CD4+ cells but a relative decrease of CD4+ T-regulatory cells.

Lymphopenia is a serious consequence of HIV infection and the administration of cancer chemotherapeutic agents. Although growth factors can be administered to patients to increase circulating neutrophils, there is no effective method to stimulate CD8+ lymphocyte production in humans, in vivo. This report is the first to describe the administration of recombinant interleukin-7 to humans and demonstrates the ability of this cytokine to mediate selective increases in CD4+ and CD8+ lymphocytes along with a decrease in the percentage of CD4+ T-regulatory cells. These studies suggest an important role for interleukin-7 in the treatment of patients with lymphopenia.

Adult↗