Department of Pathology and Laboratory Medicine, UMDNJ-New Jersey Medical School Newark, New Jersey and Southside Regional Medical Center, Petersburg, Virginia

The SOD1 mouse has a mutation of the human transgene associated with amyotrophic lateral sclerosis(ALS). Although controversial, ALS has been considered to be an autoimmune disease. From previous studies we have noticed that HUCB could effect the onset of disease and time of death in MRL Lpr/Lpr mice which is considered some-what similar to human lupus. We have determined that when HUCB is stored at 4ºC in gas permeable bags, there is a marked drop off of the mixed lymphocyte culture reaction while main-taining a significant number of cells capable of producing replatable colonies. We, therefore, attempted to determine the effect of HUCB on SOD1 mice (transgenic B65JLTgn (SOD1-G93A)1GUR), which have a mutation of the human transgene, CuZn superoxide dismutase SOD1. By combining samples and having previously developed evidence that the survival of lethally irradiated mice was related to the log of the number of human mononuclear cells (HUCB) administered, we decided to give a large dose of human mononuclear cord blood cells.
Design: The SOD1 mice develope evidence of paralysis at 4 to 5 months and the average expected lifetime of these mice is 130 days. 21 mice were divided into three groups: a control of 4 mice received no treatment; another control of 6 mice received antikiller sera, 800 cGy of irradiation and 5 x 106 bone marrow cells from congenic mice [B6SJL-TGN (SOD1) 2GUR] transgenic for the human CuZn superoxide dismutase gene but do not develop paralysis. 11 mice received antikiller sera, 800 cGy of irradiation and a total of 34.2-35.0 x 106 mononuclear cells over a two-day period obtained from HUCB previously stored for 17-20 days at 4ºC in gas permeable bags.
Results: The control mice, average age at death was 127 days. The mice receiving 800 cGy of irradiation and congenic bone marrow; average age at death was 138 days The mice receiving HUCB and irradiation was 148 days, (P<0.001 for HUCB vs. control, P<0.01 for HUCB vs. B.M) The longest surviving mouse in each group being 131, 153, 182 days respectively. In summary, large doses of HUCB mononuclear cells produced considerable delay in the onset of symptoms and death of SOD1 mice. The results although being preliminary may not only indicate that ALS is an autoimmune disease, but may also indicate a possible treatment for a devastating disease.

Human Umbilical Cord Blood Effect on SOD Mice (Amyotrophic Lateral Sclerosis)

Norman Ende, Fran Weinstein, Ruifeng Chen, Milton Ende

Department of Pathology and Laboratory Medicine, UMDNJ-New Jersey Medical School Newark, New Jersey and Southside Regional Medical Center, Petersburg, Virginia

In previous studies we observed that human umbilical cord blood (HUCB) could have a protective effect on the onset of disease and time of death in MRL Lpr/Lpr mice which have an autoimmune disease that may be considered similar to human lupus. We believed a temporary xenograph may have occurred in these animals with the disease process delayed and the life span markedly increased. When HUCB is stored at 40C in gas permeable bags, there is a decrease of the cell reaction in mixed lymphocyte cultures. The blood, however, maintains a significant number of cells capable of producing replatable colonies. This study attempted to determine the effect of HUCB on SOD1 mice (transgenic B6SJL-TgN(SOD1-G93A)1GUR), which have a mutation of the human transgene, (CuZn superoxide dismutase gene SOD1) that has been associated with amyotrophic lateral sclerosis. We previously developed evidence that the survival of lethally irradiated mice was related to the number of human mononuclear cells administered. In the present study, we decided to investigate the effect of a relatively large dose of human mononuclear cord blood cells on SOD1 mice subjected to a sublethal dose of irradiation preceded by antikiller sera (rabbit anti-asialo). The SOD1 mice show evidence of paralysis at 4 to 5 months. The average expected lifetime of these mice is reported to be 130 days (Jackson Laboratory). In this experiment, there were 23 mice. Two mice died before the onset of paralysis. The remainder were divided into three groups: group I: control group of 4 untreated mice; group II: an experimental group of 6 mice treated with antikiller sera, 800 cGy irradiation plus 5 x 106 cogenic bone marrow mononuclear cells; group III: another experimental group of 11 mice treated with antikiller sera, 800 cGy irradiation plus 34.2-35.6 x 106 HUCB mononuclear cells, previously stored for 17-20 days at 40C in gas permeable bags. The results were as follows: the average age at death was: (I) 127 days for the untreated control group, (II) 138 days for the group that received 800 cGy of irradiation and cogenic bone marrow (BM) and (III) 148 days for the group that received irradiation and HUCB. (P<0.001 HUCB vs control, p<0.01 HUCB vs BM). The longest surviving mouse in each group was 131, 153, and 182 days old respectively. In summary, large doses of HUCB mononuclear cells produced considerable delay in the onset of symptoms and death of SOD1 mice. These preliminary results may not only indicate that amyotrophic lateral sclerosis is an autoimmune disease, but may also indicate a possible treatment for a devastating disease and possibly others.

The Effect of Megadose of Human Umbilical Cord Blood (HUCB) Mononuclear Cells on Huntington Disease Mice

Norman Ende, MD New Jersey Medical School, UMDNJ, Newark, NJ 07103
Ruifeng Chen, MD New Jersey Medical School, UMDNJ, Newark, NJ 07103

Background: We have demonstrated that the use of megadose (34.2-35 x 106) of human umbilical cord blood mononuclear cells produced a significant increase in the life span of SOD1. These mice that have a mutant human transgene, CuZn super-oxide dismutase, associated with Amyotrophic Lateral Sclerosis. By raising the number of umbilical cord blood cells to 71-74 x 106 we were able to further increase the life span of SOD1 mice. Based on those finding we attempted to determine if a similar approach could be used in Huntington disease which has been postulated to have a relationship to Amytrophic Lateral Sclerosis. The mice[B6CBA-TgN(Hdexon1)62Gpb] has the human Huntington disease transgene and causes a progressive neurological phenotype in mice.
Method & Results: 24 Huntington mice were divided into 4 groups: (a). Control group of 7 untreated mice. These mice developed symptoms when they were 80 days old and were all dead by 92 days (average 86 days). (b). 5 mice received congenic bone marrow from a wild type mouse, these had a similar life span as control. (c). 5 mice, before the onset of symptom, received 71-74 x 106 mononuclear cells, 800 cGy of irradiation, anti killer sera, lived an average of 97 days.(d). 5 animals after developing neurological symptoms were given 800 cGy of irradiation, anti killer sera, 71-74 x 106 human cord blood mononuclear cells lived an average of 98 days. One animal however lived 115 days. 2 animals died within 24 hours of treatment and could not be evaluated.
Summary: The study suggests that human umbilical cord mononuclear cells given in megadose amounts with irradiation, can modify Huntington disease in mice. ( Supported by Abraham S Ende Research Foundation )

1217 - The Effect of Megadose of Human Umbilical Cord Blood Mononuclear Cells on Alzheimer's Disease Mice

N. Ende, R. Chen, D. Ende-Harris Blood Bank, New Jersey Medical School-UMDNJ

Background: Human umbilical cord blood mononuclear cells have been found to delay the onset of vasculites and prolong the life of MLR lpr/lpr mice, that have an autoimmune disease similar to Human Lupus. Recent studies have indicated that megadose of human cord blood mononuclear cells can delay the onset of symptoms of paralysis in SOD1 mice, that carry a mutant transgene for amyotrophic lateral sclerosis, for an average of 52 days. This therapy on SOD1 mice was conducted without the use of immunosuppression. We therefore decided to evaluate the effect of megadose of cord blood mononuclear cells on mice with Alzheimer’s disease without the use of immunosuppression. Design: 24 mice were divided into 3 groups (a) 9 untreated (b) 7 treated with congenic bone marrow (c) 8 treated with 105-112 x 10 6 cord blood mononuclear cells. Results: At 153 days of age: in the untreated group, 7 out of the 9 animals were dead in group (a) 6 of the 7 mice were dead in group (b), all animals were alive group (c) that received a megadose of cord blood mononuclear cells. Conclusion: Preliminary studies indicate that megadose of human umbilical cord blood mononuclear cells can significantly delay the onset of symptoms and prolong the life of Alzheimer’s disease mice. (Supported by the Abraham S. Ende Research Foundation). (Modern Pathology – Jan. 2001;Vol. 14, No. 1: 207A.)

THE BERASHIS CELL: A REVIEW IS IT SIMILAR TO THE EMBRYONIC STEM CELL?

Vol. 31, Nos. 3 & 4, 2000
Journal of Medicine

Journal of Medicine
Copyright 2000 by
PJD Publications Limited
Research Communications
Westbury, NY 11590-0966 USA

Norman Ende

Introduction