Immunomodulatory and Antimicrobial Efficacy of Intravenous Immunoglobulin in Bone Marrow Transplantation

The efficacy of IVIG in preventing GvHD has not been definitely demonstrated clinically. Using a xenogeneic model of GvHD in NOD/SCID/ccÀ (NSG) mice, we showed that weekly administration of IVIG significantly reduced the incidence and associated mortality of GvHD to a degree similar to CsA. Unlike CsA and OKT3, IVIG were not associated with inhibition of human T-cell proliferation in mice. Instead, IVIG significantly inhibited the secretion of human IL-17, IL-2, IFN-c and IL-15 suggesting that IVIG prevented GvHD by immunomodulation. Furthermore, the pattern of modification of the human cytokine storm differed from that observed with CsA and OKT3. Finally, in a humanized mouse model of immune reconstitution, in which NSG mice were engrafted with human CD34 þ stem cells, IVIG transiently inhibited B-cell reconstitution, whereas peripheral T-cell reconstitution and thymopoiesis were unaffected. Together these in vivo data raise debate related to the appropriateness of IVIG in GvHD prophylaxis. In addition, this model provides an opportunity to further elucidate the precise mechanism(s) by which IVIG inhibit GvHD.

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Use of immunoglobulins in the prevention of GvHD in a xenogeneic NOD/SCID/γc− mouse model

Gregoire-Gauthier

Durrieu

Duval

et al. 2011

“…3,[6][7][8][9][10][11] In a randomized prospective trial of 382 patients (30% were o20 years of age), the patients received 500 mg/kg weekly IVIG infusions until day 90 and then monthly until 1 year were compared with the control group. 10 The control group had a significantly higher risk of Gramnegative systemic infections, as well as local infections. Among patients X20 years of age, there was an increased risk of acute GVHD and an increased TRM.…”

Section: Discussionmentioning

confidence: 99%

Incidence and risk factors for hypogammaglobulinemia in pediatric patients following allo-SCT

Frangoul

Min²,

Wang

et al. 2013

We evaluated the incidence and risk factors for hypogammaglobulinemia after allogeneic hematopoietic SCT (HSCT) in pediatric patients. Ig levels were measured pre-transplant, every 2 weeks until day 100 and then monthly post SCT in 185 patients undergoing myeloablative HSCT. Median age was 9 years; 142 (77%) had malignant disease and 114 (62%) received stem cells from an unrelated source. Hypogammaglobulinemia (IgG o500 mg/dL) developed in 143 (77%) of the patients at a median of 56 days (range 15-339) post SCT. The cumulative incidence of hypogammaglobulinemia at 1 year was higher among patients who developed acute GVHD (97% vs 54%, Po0.001), and for those receiving stem cells from an unrelated source (94% vs 51%, Po0.001). The cumulative incidence of TRM was significantly higher for patients with hypogammaglobulinemia (P ¼ 0.026). In multivariable analysis, lower pre-transplant IgG level (Po0.001), younger age (P ¼ 0.012), diagnosis of malignant disease (Po0.001), receiving unrelated SCT (Po0.001) and development of acute GVHD (Po0.001) were all significantly associated with higher risk of hypogammaglobulinemia post HSCT. We conclude that hypogammaglobulinemia is common, following allogeneic HSCT in pediatric patients, especially in those with malignant diseases, those who receive an unrelated transplant or patients who develop GVHD. Keywords: hypogammaglobulinemia; allo-SCT; children; IVIG; IgG; GVHD INTRODUCTION Hematopoietic SCT (HSCT) is an established therapy for various malignant and non-malignant disorders in children. The recovery of the immune system after allogeneic HSCT depends on multiple variables including preparative regimen, age and the presence of GVHD. 1 In a study of 93 adult patients, the number of B cell precursors in the BM 1-year post transplant was significantly lower in patients with chronic GVHD. Neither the CD34 þ cell dose, stem cell source (BM vs peripheral blood), donor or patient age were associated with B cell recovery. 2 In another study, low immunoglobulin levels have been associated with decreased survival and increased TRM in adult patients post allogeneic HSCT. In this study, factors associated with low IgG level were age o30 years, female donor to male recipient, not receiving antithymocyte globulin in the preparative regimen and the GVHD prophylaxis regimen. 3 The authors reported a decreased survival and increased TRM in these patients. The slow recovery of immune function post SCT has been linked to poor thymic function. 4 Pediatric patients have more intact thymic function compared with adult patients, which may influence the recovery of B cell function following HSCT. Unlike adult patients, one-third of the pediatric patients undergo an allogeneic HSCT for diseases other than malignancy. Except for patients with primary immune deficiency, those patients have generally an intact immune system prior to transplant. There are no published studies examining the incidence and risk factors for hypogammaglobulinemia post myeloablative allogeneic HSCT in pediatric patients.

“…Passive immunotherapy with intravenous immunoglobulins decreases not only incidence of interstitial pneumonia and the severity of infections but also the risk of acute GVHD. 38 Bacterial endotoxins can activate cells of the monocyte macrophage system and lead to subsequent release of interleukin-1 and tumor-necrosis factor (TNF), known to enhance T cell proliferation. Endotoxin lipopolysaccharide in the cell wall of gram-negative bacteria can enter the circulation after disruption of the mucosal barrier, and can accumulate in the blood in cases of impaired hepatic clearance.…”

Section: Discussionmentioning

confidence: 99%

Use of a five-agent GVHD prevention regimen in recipients of unrelated donor marrow

Zander

Zabelina²,

Kröger

et al. 1999

Summary:A five-agent GVHD prophylaxis programme consisting of cyclosporin A, methotrexate, anti-thymocyte-globulin, pentaglobin and metronidazol was given to 48 recipients of unrelated donor marrow with chronic myelogenous leukemia, acute leukemia, myelodysplastic syndromes, and familiar lymphocytic hemophagocytosis of an average age of 33.5 (0.6-56) years. GVHD grades II-IV occurred in 18 patients (39%) and grades III-IV in five patients (11%). Chronic GVHD developed in nine patients (23%), three limited and six extensive. Fifteen patients died. Clinical relapse was detected in eight patients. Four patients died as a consequence of the underlying disease and subsequent treatment, 11 patients died of transplant-related causes. After a median follow-up of 19 months, the overall and diseasefree survival are 67% and 62%, respectively. Survival by age is as follows: 0-19 years: 12/13 patients; 20-39 years: 14/25 patients; 40-59 years: 7/10 patients. The five-agent GVHD prophylaxis regimen is effective. Matched-unrelated donor transplants can be carried out safely in patients younger than 50 years of age. The results in patients younger than 20 years of age should encourage matched-unrelated donor transplants at earlier stages of the disease.