Time course of immune recovery and viral reactivation following hematopoietic stem cell transplantation

Abstract

SummaryTotal depletion of innate and adaptive immune cell populations occurs after intensive chemotherapy and hematopoietic stem cell transplantation (HSCT) then followed by gradual recovery of immune populations, due to progenitors derived from donor hematopoietic cells which differentiate to myeloid and lymphoid lineages. Time dynamics of immune reconstitution and differential maturation of distinct immune populations is only partially evaluated, especially, at early terms post-transplant. E.g., innate immunity is restored within 1st month after HSCT, due to rapid reconstitution of granulocytes, monocytes, and natural killer (NK) cells. Meanwhile, functional recovery of mature NK-cell subsets and blood monocytes may continue for up to 3 months.Both T-and B-lymphocyte pools are restored much slower than myelomonocytic populations. The available information on their post-HSCT immune recovery is limited, since most studies are performed at later terms (>1 month post-transplant). Absolute numbers of CD8+ T cells return to control values ca. 4 months post-HSCT, however, exhibiting a skewed repertoire of memory T lymphocytes. Recovery and maturation rates of CD4+ T cells largely depend on residual thymus function, especially, in young subjects. Hence, a naïve CD4+ T cell population in pediatric patients predominates over 6 months post-HSCT. In older persons with inactive thymopoiesis the total CD4 cell counts remain low for years after HSCT. Meanwhile, antiviral cellular immunity is active since early terms post-transplant. E.g., cytotoxic CD8+ cells specific for cytomegalovirus (CMV), or Epstein-Barr virus (EBV) rapidly expand in cases of CMV or EBV activation.Despite recovery of absolute B-cell counts by day 30 post-HSCT, their functions, i.e., antigen-specific antibody production, are reduced for months and years after HSCT, due to slow restoration of mature immune cell populations, thus resemling normal evolution of B cell hierarchy in human organism.Reactivation of herpesviruses (mostly, CMV, EBV and Herpes Simplex) is a known feature of immune deficiency. Timing of maximal herpesvirus incidence (2-3 months post-HSCT) corresponds to the period of CD8+ and CD4+ T cell functional deficiency and B cell immaturity, thus reflecting their suboptimal ability to eliminate herpesvirus-affected leukocytes. Individual terms of immune recovery after allo-HSCT depend on the patients' age, source of donor cells, acute GvHD post-HSCT etc. Vaccination response, being a potent in vivo criterion of immune recovery in post-transplant patients, is also dependent on the subjects' age and restored B cell functions. Time dynamics of specific antibody response shows that the patients with latent CMV reactivation may later exhibit a strong humoral immune response, thus making the infection self-limiting.

The Role of Complement Activating Collectins and Associated Serine Proteases in Patients With Hematological Malignancies, Receiving High-Dose Chemotherapy, and Autologous Hematopoietic Stem Cell Transplantations (Auto-HSCT)

“…Septicemia is the commonest type of infection, and some patients are affected by pneumonia or alimentary tract infections ( 19 ). Post-HSCT reconstitution of bone marrow after conditioning therapy is usually attained in ~3 weeks, but full recovery of functional leukocytes takes longer ( 20 , 21 ). During the period of aplasia, patients have to be isolated, carefully monitored and receive prophylactic/supportive medication ( 4 , 18 , 22 ).…”

Stomatological problems and infectious complications after hematopoietic stem cell transplantation

“…Late oral pathology after HSCT in children is presented, mainly, by developmental anomalies of dental system in young patients. 5. Chronic graft-versus-host disease (cGVHD) is accompanied by the Sjogren-like problems with oral mucosa and salivary glands.…”

“…Quite intensive cytoreductive therapy, the so-called conditioning treatment, is administered before hematopoietic stem cell transplantation (HSCT) which causes a very deep suppression of hematopoiesis with entire depletion of granulocytes and most lymphoid cell population in peripheral blood, bone marrow and lymphoid organs. Their recovery occurs within weeks and months [5]. Along with blood cells, the cytoreductive treatment causes massive death of epithelial stem cells in oral cavity, intestines, lungs, urogenital tract etc.…”

Gut microbiome in hematopoietic stem cell transplantation: patient- and treatment-related factors

“…As fi rst step of treatment, they receive high-dose cytostatic therapy (conditioning treatment) which is usually combined with anti-infectious therapy. Th e conditioning therapy causes both acute cellular immune defi ciency which recovers within months and, even, years [1]. Moreover, severe damage of oral and intestinal epithelium develops after intensive cytostatic treatment, and massive antibacterial therapy lead to alterations of gut microfl ora composition [2].…”