Bilirubin Nanoparticle As An Anti-Inflammatory Therapy For Graft Versus Host Disease

<p>Graft versus host disease (GvHD) caused by alloreactive donor lymphocytes is a fatal complication of hematopoietic stem cell transplant (HSCT). Myeloablative conditioning regimen, consisting of chemotherapy and/or radiation, given prior to HSCT can cause tissue damage. This non-specific tissue damage triggers cross-presentation of alloantigens to the donor immune cells, causing recruitment of leukocytes and production of inflammatory cytokines. Targeting this inflammation without affecting the anti-leukemia effects of HSCT, continues to be one of the biggest challenge in finding a therapy for GvHD. Bilirubin is a tetrapyrrole pigment, found in the blood, with natural anti-oxidative and anti-inflammatory properties. Using mouse models of various inflammatory diseases, studies by our collaborating investigators have shown that, water-soluble PEGylated bilirubin nanoparticles (BRNP) selectively accumulate at the site of inflammation and prevent further tissue damage through scavenging reactive oxygen species. Therefore, we hypothesized that BRNP treatment after myeloablative conditioning regimen can reduce clinical symptoms of GvHD by abating the initial tissue damage in HSCT. We investigated the therapeutic efficacy of BRNP using murine GvHD model. Sublethally irradiated recipient mice (Balb/cJ) were infused with 5x10⁶ bone marrow cells and 5x10⁶ splenic cells from MHC-mismatched donor mice (C57/B6J) on day 1, with or without BRNP (10 mg/kg) on days 0-4. Clinical GvHD symptoms were monitored for 60 days, and mice were scored for fur, skin, posture, activity, and weight change. Untreated recipient mice (n=10) developed significantly worse GvHD (median GvHD score=3.4) compared to BRNP treated recipient mice (n=10, median GvHD score=0.3) (p=0.0003, Mann Whitney U Test). This translated into significantly better survival of BRNP treated mice with day 60 survival of 100% as compared to the untreated recipient with day 60 survival of 20% (p=0.0001, Log-rank (Mantel-Cox) Test). Histological analyses on day 8 post-transplantation, showed significantly lowered GvHD associated damage in liver, lung, skin, and gut, in BRNP treated mice as compared with untreated mice. In summary, we show that prophylactic treatment with BRNP can reduce clinical and pathological GvHD symptoms and thereby improve survival in mice. In future, we plan to investigate a treatment model of BRNP in relieving the clinical and pathological symptoms of GvHD. We also plan to explore the potential of BRNP as a drug conjugate for GvHD treatment.</p>

Name thesis:degree_name

Masters of Science (MS)

Level thesis:degree_level

Thesis (MS)

Year dc:date.available

2019

Authors dc:creator

• Pareek, Sumedha
• <p>https://orcid.org/0000-0001-6492-3849</p>

Contributors dc:contributor

• Jin Seon Im
• Jagannadha Sastry
• Seon Hee Chang

• Graft-versus-Host-Disease
• Leukemia
• Hematopoietic Stem Cell Transplantation
• Bilirubin
• Immunology and Infectious Disease
• Medicine and Health Sciences

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/964

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2011