Allogeneic Serum Eye Drops for the Treatment of Dry Eye Patients with Chronic Graft-Versus-Host Disease
Kyung-Sun Na and Man Soo Kim
Abstract
Purpose
To evaluate the therapeutic effect of allogeneic serum eye drops for the treatment of dry eye in patients with chronic graft-versus-host disease (cGVHD) following bone marrow transplantation.
Methods
Sixteen patients with cGVHD following allogeneic hematological stem cell transplantation (allo-SCT) and diagnosed with dry eye syndrome refractory to conventional treatment were prospectively enrolled in this study. Allogeneic serum eye drops were obtained from healthy related donors after serologic testing. Symptom scores, tear breakup time (tBUT), the Schirmer test without anesthesia (Schirmer I test), tear osmolarity, corneal staining score, impression cytology grade, and goblet cell densities were evaluated before and 4 weeks after administration of allogeneic serum eye drops.
Results
Enrolled patients included 6 females and 10 males between 20 and 61 years of age (mean age, 37.2±11.6 years). After 4 weeks of treatment, the Ocular Surface Disease Index (OSDI) symptom scores decreased significantly (32.5–8.9). Tear osmolarity showed a significant decrease from 311.1 to 285.1 milliosmol. The corneal staining scores significantly decreased from 2.5 to 1.8. Impression cytology grade and goblet cell density improved from 3.4 to 2.4 and from 90.6 to 122.6 cell/mm2, respectively. tBUT also significantly improved from 2.9 to 4.4 s, and the Schirmer I test results showed improvement, but lacked statistical significance (1.7–2.4 mm). No significant side effects were detected as a result of the allogeneic serum treatment during the follow-up period.
Conclusions
Allogeneic serum can be used for the treatment of severe dry eye in patients with cGVHD when autologous serum is unavailable. Care should be taken to avoid the risk of blood-borne diseases.
Umbilical cord blood transplantation: basic biology and clinical challenges to immune reconstitution.
Review article
Abstract
Allogeneic stem cell transplantation has continued to evolve as a common procedure for the treatment of hematological malignancies and bone marrow failure. Donor bone marrow and mobilized peripheral stem cells are routinely employed for the reconstitution of immune function in leukemia and lymphoma patients following radiation and/or chemotherapy. Unfortunately, only 30% of patients have an HLA-identical sibling donor and the identification of matched unrelated donors, particularly for minorities, can present an exceptional challenge. The transplantation of umbilical cord blood (UCB) represents the most recent strategy to expand the potential donor pool while maintaining an acceptable level of treatment-related complications. First utilized in children, UCB transplantation permits a higher degree of HLA disparity while demonstrating a reduction in the incidence and severity of graft-versus-host disease (GvHD) compared to previous transplantation modalities. Despite the apparent decrease in GvHD, relapse rates remain comparable to transplantation with bone marrow or mobilized peripheral blood suggesting a strong graft-versus-leukemia/lymphoma (GvL) effect. However, several issues complicate the use of UCB transplantation and its extension to the treatment of adults. Many infections that afflict transplant patients are particularly frequent and more severe in the context of UCB transplantation. UCB T-cells are naive and therefore display less proliferation and IFN-gamma production in response to cognate antigen and also appear to demonstrate defects in signal transduction mechanisms. In addition, UCB contains T regulatory cells (Treg) with more potent suppressor function than adult Treg. Furthermore, adult patients often require more total cells and CD34+ progenitors for transplantation than a single UCB unit can provide. Thus, strategies to expand selected subpopulations from UCB and the use of multi-unit transplantation are areas of active research. This review will provide a condensed summary of the clinical history of UCB transplantation and emphasize the advantages and disadvantages of this approach to hematological malignancies in comparison to other methods of hematopoietic stem cell transplantation. Subsequently, it will mainly focus on the current challenges to immune reconstitution presented by UCB transplantation, recent research into their cellular and molecular mechanisms, and experimental approaches to overcome them.
By Richard Duggleby, Steve Cox, J Alejandro Madrigal and Aurore Saudemont
Submitted: March 23rd 2016Reviewed: July 18th 2016Published: January 11th 2017
DOI: 10.5772/64945
Downloaded: 611
Abstract
Umbilical cord blood (UCB) has been increasingly used as a source of haematopoietic stem cells (HSCs) for transplantation. UCB transplantation (UCBT) has some advantages such as less stringent human leucocyte antigen (HLA) matching and lower impact of graft-versus-host disease (GvHD). UCBT is also characterised by a high rate of infections, graft failure, delayed engraftment and slow recovery of the immune system. UCB contains HSC as well as immune cells that could be considered to develop new treatments for the main complications post-UCBT but also to treat other diseases. GvHD remains a major complication post-CBT and post-haematopoietic stem cell transplantation (HSCT). In view of their ability to induce tolerance and suppress the functions of effector T cells, regulatory T (Treg) cells have been proposed as an adoptive therapy to modulate GvHD post-HSCT. In addition, we showed that UCB contains soluble NKG2D ligands that can modulate the functions of NKG2D expressing cells, making UCB plasma a product of interest to modulate inflammation and in particular skin GvHD. Here, we aim to describe some of the therapies currently developed using UCB, focusing on Treg cells and UCB plasma for the treatment of GvHD.
Graft-versus-host Disease After Double-Unit Cord Blood Transplantation Has Unique Features and an Association with Engrafting Unit-Recipient HLA-match
D. M. Ponce, A. Gonzales, […], and J. N. Barker
Abstract
Manifestations and risk factors of graft-versus-host disease (GVHD) after double-unit cord blood transplantation (DCBT) are not firmly established. We evaluated 115 DCBT recipients (median age 37 years) transplanted for hematologic malignancies with myeloablative or non-myeloablative conditioning and calcineurin-inhibitor/ mycophenolate mofetil immunosuppression. Incidences of day 180 grade II–IV and III–IV acute GVHD (aGVHD) were 53% (95%CI: 44–62) and 23% (95%CI: 15–31), respectively, with a median onset of 40 days (range 14–169). Eighty percent of patients with grade II–IV aGVHD had gut involvement, and 79% and 85% had day 28 treatment responses to systemic corticosteroids or budesonide, respectively. Of 89 engrafted patients cancer-free at day 100, 54% subsequently had active GVHD with 79% of those affected having persistent or recurrent aGVHD or overlap syndrome, whereas late GVHD in the form of classical chronic GVHD was uncommon. Notably, grade III–IV aGVHD incidence was lower if the engrafting unit human leukocyte antigen (HLA)-A,-B,-DRB1 allele match was > 4/6 to the recipient (HR 0.385, p = 0.031), whereas engrafting unit infused nucleated cell dose and unit-unit HLA-match were not significant. GVHD after DCBT was common in our study, predominantly affected the gut, had a high therapy response, and late GVHD frequently had acute features. Our findings support the consideration of HLA- A,-B,-DRB1 allele donor-recipient (but not unit-unit) HLA-match in unit selection, a practice change in the field. Moreover, new prophylaxis strategies that target the gastrointestinal tract are needed
Original Article | Published:
Cord Blood Stem Cells
Impact of ABO-mismatch on risk of GVHD after umbilical cord blood transplantation
Bone Marrow Transplantation volume48, pages1046–1049 (2013) | Download Citation
Recent advances in allogeneic hematopoietic cell transplant (allo-HCT) have led to an increasing use of alternative donors, including banked umbilical cord blood (UCB). Despite these advances, acute GVHD (aGVHD) and chronic GVHD (cGVHD) continue to be the leading causes of early and late transplant-related mortality. ABO-mismatch has been frequently reported as a risk factor for GVHD, however, data in the UCB recipients are limited. We hypothesized that as the lymphocytes in the cord blood are thought to be naive, they will therefore be less likely to mediate GVHD. Therefore, we analyzed the impact of ABO-mismatch on aGVHD and cGVHD in recipients of single and double UCB-HCT. In both univariate and multivariate analyses, presence of ABO-mismatch did not have an impact on aGVHD or cGVHD. Whereas ABO-compatible donors are preferred in recipients of URD-HCT, ABO compatibility generally need not be considered in recipients of UCB-HCT
[Umbilical cord blood as a source of stem cells].
Review article
Abstract
Umbilical cord blood (UCB) is a source of the rare but precious primitive hematopoietic stem cells (HSC) and progenitor cells that can reconstitute the hematopoietic system in patients with malignant and nonmalignant disorders treated with myeloablative therapy. UCB cells possess an enhanced capacity for progenitor cell proliferation and self-renewal in vitro. UCB is usually discarded, and it exists in almost limitless supply. The blood remaining in the delivered placenta is safely and easily collected and stored. The predominant collection procedure currently practiced involves a relatively simple venipuncture, followed by gravity drainage into a standard sterile anti-coagulant-filled blood bag, using a closed system, similar to the one utilized on whole blood collection. After aliquots have been removed for routine testing, the units are cryopreserved and stored in liquid nitrogen. UCB banks are being established throughout the world and UCB units are collected for allogeneic unrelated and related HSC transplantation. In unrelated cord blood banks donated UCB units are collected and stored for allogeneic use in patients who do not have an identified HLA matched relative. UCB banks report available units to national and international donor registries. The second model of UCB banking is referred to as family banking, where UCB is stored for the benefit of the donor or their family members. After more than one decade of clinical experience, it is currently accepted that UCB transplants, related and unrelated, are equivalent to or might compare favorably with bone marrow (BM) transplants, especially in children. Initial studies of long-term survival in children with both malignant and non-malignant hematologic disorders, who were transplanted with UCB from a sibling donor, demonstrated comparable or superior survival to children who received BM transplantation. One factor that limits the use of UCB transplantation in adult patients is the relatively limited number of HSC that may be harvested from umbilical cord, resulting in a slower time to engraftment and higher transplant related mortality, mainly due to the long aplasia period after transplantation and susceptibility to viral and fungal infections. Despite prolonged periods of aplasia, the apparent reduction in the incidence and severity of graft versus host disease (GVHD) may in turn underline comparable rates of survival in some series comparing UCB to adult-donor sources. The “naive” nature of UCB lymphocytes may explain the lower incidence and severity of GVHD encountered in UCB transplantation compared to the allogeneic BM transplant setting. UCB transplantation does not seem to be associated with increased rates of disease relapse. The available data suggest that nucleated cell dose in UK unit should be the primary criterion for donor selection. In 1991, the UCB transplantation program was established at the Zagreb University Hospital Center for related transplants, and until now 4 UCB transplantations have been performed successfully. In order to speed up the engraftment rate, several strategies such as multiple UCB transplants and ex vivo expansion of HSC have been assayed. The current strategies are focused on the development of much more efficient technologies for ex vivo production of progenitor cells, but whether expansion will speed engraftment and improve outcome after UCB remains to be determined. UCB is known to contain extremely immature stem cells. Consequently, such pluripotent or, perhaps, multipotent stem cells have been proposed as elements suitable for cellular therapy and regenerative medicine. Up to date there are no conclusive data regarding these possibilities but preliminary in vitro and animal studies in the field of tissue regeneration suggest some degree of plasticity and/or transdifferentiation. UCB cells are showing their unique qualities and potential, and consequently UCB banks might dramatically increase the scope of their clinical application.