Lactoferrin Accelerates Reconstitution of the Humoral and Cellular Immune Response During Chemotherapy-induced Immunosuppression and Bone Marrow Transplant in Mice

Abstract

Experimental evidence from previous studies supports the conclusion that orally administered lactoferrin (LF) restores the immune response in mice treated with a sublethal dose of cyclophosphamide (CP). The aim of this study was to elucidate potential benefit of LF in mice undergoing chemotherapy with busulfan (BU) and CP, followed by intravenous (i.v.) injection of bone marrow cells. CBA mice were treated orally with busulfan (4 mg/kg) for 4 consecutive days, followed by two daily doses of CP delivered intraperitoneally (i.p.) at a dose of 100 mg/kg and reconstituted next day with i.v. injection of 10(7) syngeneic bone marrow cells. One group of these mice was given LF in drinking water (0.5% solution). After treatment, mice were immunized with ovalbumin (OVA) to subsequently measure delayed type hypersensitivity responsiveness and with sheep red blood cells to determine humoral immunity by evaluation of splenic antibody-forming cells. As expected, both humoral and cellular immune responses of mice that were treated with these chemotherapeutic agents was markedly impaired. Here we report that this impairment was remarkably attenuated by oral administration of LF. Humoral immunity fell to levels that were 66-88% lower than that of untreated animals. Humoral immunity of LF-treated animals was equivalent to that of untreated mice within 1 month. Cellular immune responses were inhibited by chemotherapy treatment to a lesser degree, reaching levels that were approximately 50% lower than those of untreated animals. Again, LF mitigated this decrease, resulting in responses that were only slightly lower than those observed in untreated animals. Furthermore, when mice were given a lethal dose of BU (4 x 25 mg daily doses, i.p.) followed by a bone marrow transplant, LF caused enhanced lympho-, erythro-, and myelopoiesis in the bone marrow and appearance of transforming splenic lymphoblasts, similar to effects caused by administration of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF). In summary, our study suggests that LF may be a useful agent to accelerate restoration of immune responsiveness induced by chemotherapy in bone marrow transplant recipients.

Efficacy and Safety of Oral Lactoferrin Supplementation in Combination with rHuEPO-β for the Treatment of Anemia in Advanced Cancer Patients Undergoing Chemotherapy: Open-Label, Randomized Controlled Study

“…Apart from having specific and established immune-modulating activities [27,28], it also has specific antineoplastic actions in vitro and in vivo [29]. The latter should not be underestimated, especially in light of recent reports [30 -34] of a possible proneoplastic effect of ESAs, which could thus be partly counteracted or balanced.…”

Homologous Lactoferrin Triggers Mobilization of the Myelocytic Lineage of Bone Marrow in Experimental Mice

“…For example, a stimulation of myelopoiesis by pretreatment of mice with LF was demonstrated in bacteremia, which was associated with protection [33]. Similarly, in mice subjected to chemotherapy and bone marrow transplant, the bone marrow was more rapidly repopulated in LF treated than in control mice [41]. On the other hand, in mice given a sublethal dose of cyclophosphamide (CP), LF inhibited a rebound in CP-induced neutrophilia and eosinophilia and led to normalization of the blood picture (increased percentage of lymphocytes) [42].…”

Requirement for IFN-γ, CD8+ T Lymphocytes, and NKT Cells in Talactoferrin-Induced Inhibition of neu+ Tumors

“…Because oral TLF does not manifest systemic adverse effects (it has been administered to over 475 people without a single drug-related serious adverse event), it promises a more favorable efficacy/ toxicity trade-off than conventional chemotherapy. In addition, oral lactoferrin has been shown to help protect against common adverse events associated with chemotherapy including cytopenias (39) and gut toxicities (40).…”