Common lymphoid progenitors rapidly engraft and protect against lethal murine cytomegalovirus infection after hematopoietic stem cell transplantation

Abstract

Lymphoid deficiency after allogeneic hematopoietic cell transplantation (HCT) results in increased susceptibility to infection; however, transplantation of mature lymphocytes frequently results in a serious complication known as graft-versushost disease (GVHD). Here we demonstrate in mice that both congenic as well as allogeneic transplantation of low numbers of highly purified common lymphoid progenitors ( IntroductionMyeloablative doses of chemoradiation therapy used in preparation for hematopoietic cell transplantation (HCT) lead to depletion of hematopoietic stem cells (HSCs), progenitor cells, and mature cells. The resulting immunodeficiency results in a profound susceptibility to bacterial, fungal, and viral infections. The recovery of a functional immune system after HCT is dependent upon the de novo regeneration of all hematopoietic lineages from HSCs and progenitor cells and on the function of mature cells contained in the graft. Infections after HCT typically follow a reproducible temporal pattern correlating with the kinetics of immune reconstitution. Viral infections occur later during the phase of lymphoid deficiency resulting from reactivation of herpesviruses such as cytomegalovirus (CMV), varicella zoster, and Epstein-Barr virus. 1 T-and B-cell deficiency is usually protracted, resolving only after several months to years. The nature of the immunodeficiency following allogeneic HCT is further complicated by the potential to develop graft-versushost disease (GVHD), which has been shown to contribute to thymic stroma perturbations, lymphoid hypoplasia, and B-cell dysfunction. [2][3][4][5][6] Consequently, GVHD and the resultant administration of immunosuppressive agents are both associated with a significantly increased risk of lethal infectious complications.One of the most common and potentially lethal manifestations of lymphoid deficiency is infection with CMV. 7 Therefore, numerous clinical and animal studies were undertaken to characterize the complex immune response to CMV and to develop treatment strategies involving antiviral drugs as well as cellular therapies and vaccination. 8,9 Although advances were made, new strategies to prevent infections after HCT while minimizing GVHD are still warranted. We propose that modifying grafts by inclusion of committed progenitor cells can be used to protect against infections. 10 Hematopoietic cell populations at different levels of commitment have been phenotypically identified in both mice and humans and can be prospectively isolated. These populations include HSCs, common lymphoid progenitors (CLPs), common myeloid progenitors (CMPs), and, downstream of CMPs, granulocyte-monocyte progenitors (GMPs) and megakaryocyte-erythroid progenitors (MEPs). [11][12][13][14][15][16][17] In vivo studies using competitive reconstitution assays in congenic mice showed that transplantation of CLPs, CMPs, GMPs, or MEPs resulted in accelerated reconstitution of the respective mature cell compartments compared with transplantation of HSCs alone. 13,16 Our studies show...

Acute lymphoblastic leukemia with the phenotype of a putative B‐cell/T‐cell bipotential precursor

“…The cells are of particular interest to clinicians as a potential tool for the augmentation of immune reconstitution following stem cell transplantation [16,17]. Our patient may provide further corroborative evidence for the existence of the CLP in humans.…”

Immune restoration following hematopoietic stem cell transplantation: an evolving target

“…184 Similarly, murine lymphoid progenitor cells have also been shown to confer protection against infection, specifically CMV. 185 As these cells are derived from HSCs, further study of these progenitor cells and their immunomodulatory effects may reveal novel ways of HSC regulation and alternative approaches to their expansion.…”

Rapid Lymphocyte Reconstitution of Unconditioned Immunodeficient Mice with Non-Self-Renewing Multipotent Hematopoietic Progenitors

“…For instance, studies using common lymphoid progenitors have shown that a rapid burst of lymphopoiesis can protect mice against lethal doses of cytomegalovirus after irradiation and HSC transplantation. 10 To test the ability of non-self-renewing progenitors to generate immunity in unconditioned immunocompromised recipients, we transplanted 180 c-kit+ lineage-Sca-1+ flk2+ (KLS flk2+) progenitor cells or 500 c-kit+ lineage-Sca-1+ CD34-flk2-HSCs into unconditioned recombinase activating gene 2 and interleukin-2 receptor common gamma chain-deficient (RAG2 -/-γc -/-) mice. 11 These KLS flk2+ cells retain myeloid and lymphocytic differentiation potential, but lack the ability to self-renew for the lifetime of the organism.…”