title: National Institutes of Health Hematopoietic Cell Transplantation Late Effects Initiative: The Immune Dysregulation and Pathobiology Working Group Report.
abstract: Immune reconstitution after hematopoietic stem cell transplantation (HCT) beyond 1 year is not completely understood. Many transplant recipients who are free of graft-versus-host disease (GVHD) and not receiving any immunosuppression more than 1 year after transplantation seem to be able to mount appropriate immune responses to common pathogens and respond adequately to immunizations. However, 2 large registry studies over the last 2 decades seem to indicate that infection is a significant cause of late mortality in some patients, even in the absence of concomitant GVHD. Research on this topic is particularly challenging for several reasons. First, there are not enough long-term follow-up clinics able to measure even basic immune parameters late after HCT. Second, the correlation between laboratory measurements of immune function and infections is not well known. Third, accurate documentation of infectious episodes is notoriously difficult. Finally, it is unclear what measures can be implemented to improve the immune response in a clinically relevant way. A combination of long-term multicenter prospective studies that collect detailed infectious data and store samples as well as a national or multinational registry of clinically significant infections (eg, vaccine-preventable severe infections, opportunistic infections) could begin to address our knowledge gaps. Obtaining samples for laboratory evaluation of the immune system should be both calendar and eventdriven. Attention to detail and standardization of practices regarding prophylaxis, diagnosis, and definitions of infections would be of paramount importance to obtain clean reliable data. Laboratory studies should specifically address the neogenesis, maturation, and exhaustion of the adaptive immune system and, in particular, how these are influenced by persistent alloreactivity, inflammation, and viral infection. Ideally, some of these long-term prospective studies would collect information on long-term changes in the gut microbiome and their influence on immunity. Regarding enhancement of immune function, prospective measurement of the response to vaccines late after HCT in a variety of clinical settings should be undertaken to better understand the benefits as well as the limitations of immunizations. The role of intravenous immunoglobulin is still not well defined, and studies to address it should be encouraged.
authors.affiliation: Experimental Transplantation and Immunology Branch, National Cancer Institute, Bethesda, Maryland. Electronic address: banacloj@mail.nih.gov.
authors.forename: Juan
authors.initials: J
authors.lastname: Gea-Banacloche
authors.affiliation: Sylvester Adult Stem Cell Transplant Program, University of Miami, Coral Gables, Florida.
authors.forename: Krishna V
authors.initials: KV
authors.lastname: Komanduri
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; University of Washington School of Medicine Pediatrics, Seattle, Washington.
authors.forename: Paul
authors.initials: P
authors.lastname: Carpenter
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Sophie
authors.initials: S
authors.lastname: Paczesny
authors.affiliation: Division of Hematological Malignancies and Cellular Therapy, Duke University Department of Medicine and Duke Cancer Institute, Durham, North Carolina.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Sarantopoulos
authors.affiliation: Division of Infectious Diseases and International Medicine, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Jo-Anne
authors.initials: JA
authors.lastname: Young
authors.affiliation: National Heart, Lung and Blood Institute, Bethesda, Maryland.
authors.forename: Nahed
authors.initials: N
authors.lastname: El Kassar
authors.affiliation: Medical Officer, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland.
authors.forename: Robert Q
authors.initials: RQ
authors.lastname: Le
authors.affiliation: Professor of Pediatrics, UBC, Michael Cuccione Childhood Cancer Research Program, BC Children's Hospital and Research Institute, Vancouver, Canada.
authors.forename: Kirk R
authors.initials: KR
authors.lastname: Schultz
authors.affiliation: Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Griffith
authors.affiliation: Long Term Transplant Clinic, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Bipin N
authors.initials: BN
authors.lastname: Savani
authors.affiliation: University of Florida Health Cancer Center, Gainesville, Florida; Bone Marrow Transplant Program, Division of Hematology/Oncology, University of Florida College of Medicine, Gainesville, Florida.
authors.forename: John R
authors.initials: JR
authors.lastname: Wingard
mesh_terms: D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D000074243:Immune Reconstitution / Q000502:physiology*; D007239:Infections / Q000209:etiology / Q000628:therapy; D000069451:Long Term Adverse Effects / Q000628:therapy; D009316:National Institutes of Health (U.S.); D014481:United States
keywords: Immune reconstitution; Immunization; Intravenous immunoglobulin; Late infections