Rheumatoid Arthritis is a pain in her … while Kathy Molnar-Kimber is a Scientist, Inventor, Invited Speaker, Teacher, Consultant, Patient and Writer.

Dr. Kathy Molnar-Kimber explains that rheumatoid arthritis is considered an autoimmune disease because your immune system plays a major role in the inflammation in your joints.

Here’s more about my research experience, and I as a scientist, speaker, teacher, consultant and writer.

I initially investigated how the immune system works in mice during graduate school.

Both our immune system and the immune system of mice work very similarly.

Of my over 50 publications, the first six showed that a special gene complex in mice, called Mls, induces many T cells to multiply or grow because the T cells recognize Mls in a different way than regular antigens. Since this time, several other labs have identified other antigens, such as the proteins that cause toxic shock syndrome, that cause many T cells to grow or proliferate in a similar manner.

1. Molnar-Kimber, K.L. and Sprent, J. (1980). Absence of H-2 restriction in primary and secondary mixed lymphocyte reactions to strong Mls determinants. J. Exp. Med. 151: 407-417.

2. Molnar-Kimber, K.L., Webb, S.R., Sprent, J. and Wilson, D.B. (1980). T-cell lines with dual specificity for strong Mls and H-2 determinants. J. Immunol. 125: 2643-2645.

3. Sprent, J., Korngold, R. and Molnar-Kimber, K.L. (1980). T-cell recognition of antigen in vivo: role of the H-2 complex. In: Seminars in Immunopathology, Vol. III: Communication Between Subsets of Lymphocytes. (Ed. K. Eichmann). Springer-Verlag. pp. 213-245.

4. Molnar-Kimber, K.L., and Sprent, J. (1981). Evidence that strong Mls determinants are nonpolymorphic. Transplantation 31: 376-378.

5. Webb, S.R., Molnar-Kimber, K.L., Bruce, J., Wilson, D.B. and Sprent, J. (1981). T-cell clones with specificity for Mls and various major histocompatibility complex determinants. J. Exp. Med. 154: 1970-1974.

6. Webb, S.R., Bruce, J., Molnar-Kimber, K.L., Wilson, D.B. and Sprent, J. (1982). Anti-H-2 reactivity of Mls-specific T-cell clones. In: Isolation, Characterization and Utilization of T-Lymphocytes. Academic Press. pp. 331-339.

I’ve next investigated how some infectious agents grow using molecular biology, virology and cell biology methodology.

7. Molnar-Kimber, K.L., Summers, J., Taylor, J.M. and Mason, W.S. (1982). A protein is covalently-bound to minus strand DNA intermediates of duck hepatitis B virus. J. Virol. 45: 165-172.

8. Halpern, M.S., England, J.E., Deery, D.T., Petcu, D.J., Mason, W.S. and Molnar-Kimber, K.L. (1983). Viral nucleic acid synthesis and antigen accumulation in pancreas and kidney of Pekin ducks infected with duck hepatitis B virus. Proc. Natl. Acad. Sci. (U.S.A.) 80: 4865-4869.

9. Molnar-Kimber, K.L., Summers, J. and Mason, W.S. (1984). Mapping of the cohesive overlap of duck hepatitis B virus DNA and of the site of initiation of reverse transcription. J. Virol. 51: 181-191.

10. Mason, W.S., Halpern, M.S., Newbold, J., Rogler, C., Molnar-Kimber, K.L. and Summers, J. (1985). Molecular Biology of the replication of Hepatitis B viruses. In: Viruses and Cancer. (Eds. P.W.J.Rigley and N.M. Wilkie). pp. 23-42.

My research interests then focused on how mice and other animals wage war against infectious agents.

I played an integral role in the generation of several vaccine candidates from Wyeth, although none of these are currently marketed.

Design, Characterization and Development of new types of vaccines for Hepatitis B Virus and HIV, the cause of AIDS.

11. Molnar-Kimber, K.L., Davis, A.R., Jarocki-Witek, V., Lubeck, M.D., Vernon, S.K., Conley, A.J. and Hung, P.P. (1987). Characterization and assembly of Hepatitis B envelope proteins expressed by recombinant adenoviruses. In: Hepadna Viruses (Eds. W. Robinson, K. Koike and H. Will). Alan R. Liss, Inc., New York. pp. 173-187.

12. Hung, P.P., Morin, J.E., Lubeck, M.D., Barton, J.E., Molnar-Kimber, K.L., Mason, B.B., Dheer, S.K., Jarocki-Witek, V., Kostek, B., Zandle, G., Conley, A.J. and Davis, A.R. (1987). Recombinant adenovirus as a vehicle for the HBV surface antigen or HIV envelope protein genes. In: Human Retroviruses, Cancer and AIDS: Approaches to Prevention and Therapy. (Ed. D. Bolognesi). Alan R. Liss, Inc. New York. pp. 349-361.

13. Mason, B.B., Morin, J.E., Davis, A.R., Conley, A.J., Lubeck, M.D., Molnar-Kimber, K.L., Chengalvala, M., Bhat, B., Dheer, S.K., Hum, W.T. and Hung, P.P. (1988). In: Current Communications in Molecular Biology: Viral Vectors. (Eds. Y. Gluzman and S.H. Hughes). Cold Spring Harbor Laboratories, Cold Spring Harbor, NY. pp.51-55.

14. Chanda, P.K., Natuk, R.J., Greenberg, L., Mason, B.B., Bhat, B.M., Dheer, S. K., Morin, J.E., Molnar-Kimber, K.L., Mizutani, S., Lubeck, M.D., Davis, A.R. and Hung, P.P.. (1988). Expression of HIV Envelope Glycoproteins by Non-Defective Adenovirus Vector. In: Approaches to Modern vaccines. (Ed. H.Ginsberg). Cold Spring Harbor Laboratories, Cold Spring Harbor, NY. pp. 207-212.

15. Molnar-Kimber, K.L., Jarocki-Witek, V., Vernon S.K., Conley, A.J., Davis, and Hung, P.P. (1988). Distinctive Properties of Hepatitis B envelope proteins expressed by Recombinant Adenoviruses. J. Virol. 62: 407-416.

16. Hung, P.P., Morin, J.E., Lubeck, M.D., Barton, J.E., Molnar-Kimber, K.L., Mason, B.B., Dheer, S.K., Jarocki-Witek, V., Kostek, B., Zandle, G., Conley, A., and Davis, A.R. (1988) Expression of HBV Surface Antigen or HIV Envelope Protein Using Recombinant Adenovirus Vectors. Nat. Immunity Cell Growth Regul. 7:135-143.

17. Molnar-Kimber, K.L., Lubeck, M.D., Haigwood, N.L., Najarian, R., Moore, G.K., Jarocki-Witek, V., Morin, J.E., Chengalvala, M., Stauffer, B., Mason, B.B., Bhat, B.M., Mizutani, S., Conley, A.J., Davis, A.R. and Hung, P.P. (1989). Characterization and utilization of the E3 regions of Ad4 and Ad7 for development of live recombinant adenovirus vaccine for hepatitis B virus. In: Approaches to Modern Vaccines. (Eds. F.Brown, R.M.Chanock, H.S.Ginsberg and R.A.Lerner). Cold Spring Harbor Laboratories., Cold Spring Harbor, NY. pp. 383-388.

18. Lubeck, M.D., Davis, A.R., Chengalvala, M., Natuck, R., Morin, J.E., Molnar-Kimber, K.L., Mason, B.B., Mizutani, S., Hung, P.P. and Purcell, R.H. (l989). Immunogenecity and Efficacy Testing in Chimpanzees of an Oral Hepatitis B virus Vaccine Based Upon Live Recombinant Adenovirus. Proc. Natl. Acad. Sci. 86: 6763-6767.

19. Chanda, P.K., Natuk, R.J., Mason, B.B., Bhat, B.M., Greenberg, L., Dheer, S. K., Molnar-Kimber, K.L., Mizutani, S., Davis, A.R., Lubeck, M.D. and Hung, P.P. (1990). High Level expression of the envelope glycoproteins of the Human Immunodeficiency Virus type 1 (HIV-1) using Recombinant Adenovirus vectors. Virology 175: 535-547.

20. Mason, B.B., Davis, A.R., Bhat, B., Zandle, G., Kostek, B., Choldofsky, S., Dheer, S., Chengalvala, M., Molnar-Kimber, K.L., Mizutani, S., and Hung, P.P. (l990). Analysis of the Role of the First Intervening Sequence of the Adenovirus Tripartite Leader in the Expression of Hepatitis B Surface Antigen Using Helper Independent Adenovirus Type 4 and Adenovirus Type 7 Recombinants. Virology 176: 452-461.

21. Morin, J.E., Lubeck, M.D., Mason, B.B., Molnar-Kimber, K.L., Dheer, S.K., Bhat, B.M., Chanda, P.K., Natuk, R.J., Chengalvala, M., Mizutani, S., Davis, A.R. and P.P. Hung. (1990). In: The Molecular Approach to New and Improved Vaccines. (Eds. G.C.Woodrow and M. Levine). Marcel Dekker, Inc., New York. pp.448-457.

22. Chengalvala, M., Lubeck, M.D., Davis, A.R., Mizutani, S., Molnar-Kimber, K.L., Morin, J. and Hung, P.P. (1991). Evaluation of adenovirus type 4 and 7 recombinant Hepatitis B vaccines in dogs. Vaccine 9: 485-490.

Some compounds affect the immune system, by changing TNFalpha and IL-1ß production.

You’re probably very aware of biological response modifiers that block TNF alpha activity because they are often prescribed for rheumatoid arthritis patients. They’re called Enbrel, Remicade or Humira.

Although I did not work on the development of these biological response modifiers, I studied the effect of other drugs, namely phosphodiesterase type IV inhibitors on TNF alpha and IL-1 beta production. While none of the PDE IV compounds I studied are currently used in the clinic, other phosphodiesterase inhibitors (type V inhibitors developed by Pfizer such as Viagra) are used today.

23. Molnar-Kimber, K.L., Yonno, L., Heaslip, R.J. and Weichman, B.M. (1992). Differential Regulation of TNF alpha and IL-1 beta production from endotoxin stimulated monocytes by phosphodiesterase inhibitors. Mediators of Inflammation 1: 411-417.

24. Heaslip, R.J., Sturm R.J., Molnar-Kimber, K.L. and Weichman, B.M. (1992). The potential role of isozyme-selective phosphodiesterase inhibitors in the treatment of asthma and other inflammatory disorders. In: Proceedings of the 10th Immunopharmacology Symposium of Japan, "New Possibilities of anti-asthma and anti-allergic agents".

25. Lewis, A.J., Glaser, K.B., Sturm, R.J., Molnar-Kimber, K.L. and Bansbach, C.C. (1992) Strategies for the development of new antiarthritic agents. Int. J. Immunopharmac. 14: 497-504.

26. Molnar-Kimber, K.L., Yonno, L., Heaslip, R.J. and Weichman, B.M. (1993). Modulation of TNFalpha and IL-1 beta from endotoxin-stimulated monocytes by selective PDE isozyme inhibitors. Agents and Actions 39: C77-79.

Rapamycin, also called Rapamune, and sirolimus is currently used for blocking rejection of kidney graft rejection.

It is an immunosuppressant and an anti-cancer agent. Some other immunosuppressants such as cyclosporine are occasionally used for rheumatoid arthritis.

I contributed to rapamycin’s development in these papers and other studies described in several patents. In collaboration, we identified the effector protein of rapamycin which was a hotly pursued target.

27. Chen, Y., Zhou, P., Berova, N., Zhang, H., Nakanishi, K., Failli, A., Steffan, R., Molnar-Kimber, K.L. and Caggiano, T.J. (1994). Circular Dichroic Studies on the Binding of rapamycin and analogs to FKBP: Application of Second Derivative Spectroscopy. JACS 116: 2683-2684.

28. Chen, Y., Chen, H., Rhoad, A.E. Warner, L., Caggiano, T., Failli, A., Zhang, H., Hsiao, C.L., Nakanishi, K. and Molnar-Kimber, K. L. (1994). Isolation of A Putative Sirolimus (Rapamycin) Effector Protein. Biochem. Biophys. Res. Commun. 203: 1-7.

29. Sehgal, S.N., Molnar-Kimber, K.L., Ocain, T. and Weichman, B. (1994). Rapamycin, a novel immunosuppressive macrolide. Med. Res. Rev. 14:1-22.

30. Molnar-Kimber, K.L., Rhoad, A., Warner, L., Chen, H., and Sehgal, S.N. (1995) Comparison of effects of sirolimus on cytokine dependent and cytokine independent proliferation. Inflammation Research, 44: S189-190.

31. Chen, Y., Nakanishi, K., Merrill, D., Eng, C. P., Molnar-Kimber, K. L., Failli, A., Caggiano, T. J. (1995) Synthesis and bioactvity of photolabile sirolimus (rapamycin) analogs. Bioorganic and Medicinal Chemistry Letters, 5:1355-1358.

32. Molnar-Kimber, K.L. and Sehgal, S.N. (1995) Rapamycin (Sirolimus, Rapamune), a novel immunosuppressive agent. Immunopharmaceuticals Ed. Edward Kimball, CRC Press, p. 31-64. 33. Molnar-Kimber, K.L. (1996) Mechanism of Action of Rapamycin. Transplantation Proceedings 28: 964-969.

Patent applications on rapamycin:

Molnar-Kimber, K.L., Ocain, T., Vernon, S.K., and Huang, J. Biotin Esters of Rapamycin. US patent # 5,504,091. Issued Apr. 2, 1996.

Caggiano,T, Chen, Y., Failli, A., Molnar-Kimber, K.L., Nakanishi, K. Effector Proteins of Rapamycin. U.S. patent #6,313,264B1. Issued Nov. 6, 2001.

Caggiano,T, Chen, Y., Failli, A., Molnar-Kimber, K.L., Nakanishi, K. Effector Proteins of Rapamycin. U.S. patent #6,713,607, Mar. 30, 2004.

Molnar-Kimber, K.L., Caufield, C.E., and Failli, A. Rapamycin position 27 conjugates and antibodies. U.S. patent #6,328,970. Issued Dec. 12, 2001.

Molnar-Kimber, K.L., Caufield, C.E., Ocain, T. and Failli, A. Monoclonal antibodies obtained using rapamycin position 27 conjugates as an immunogen. U.S. patent #6,541,612. Issued April 1, 2003.

Here, we explored how genetically modified Herpes simplex viruses and Adenoviruses can destroy cancers, such as mesothelioma, lung cancer, ovarian cancer, colon cancer, and thyroid cancer.

My laboratory also measured how the immune system of human patients responded to the adenovirus based gene therapy.

34. Kucharczuk, J.C., Randazzo, B., Chang, M.Y., Amin, K.M., Elshami, A.A., Sterman, D.H., Rizk, N. P., Molnar-Kimber, K.L., Brown, S. M., MacLean, A.R., Litsky, L.A., Fraser, N. W., Albelda, S.M., and Kaiser, L.R. (1997) Use of a Replication-Restricted, Recombinant Herpes Virus to Treat Localized Human Malignancy. Cancer Research 57, 466-471.

35. Elshami, A.A., Cook, J.W., Amin, K.M., Choi, H., Park, J.Y., Coonrod, L., Sun, J., Molnar-Kimber, K.L., Wilson, J.M., Kaiser, L.R., and Albelda, S.M. (1997) The effect of promoter strength in adenoviral vectors containing herpes simplex virus thymidine kinase on cancer gene therapy in vitro and in vivo. Cancer Gene Therapy 4, 213-227.

36. Sterman,D.H., Treat, J., Litzky, L.A., Amin, K.M., Molnar-Kimber, K.L., Wilson, J.M., Albelda, S.M. and Kaiser, L.R. (1998) Adenovirus-mediated Herpes simplex virus thymidine kinase gene delivery in patients with localized malignancy: Results of a Phase 1 Clinical Trial for Mesothelioma. Human Gene Therapy 9:1083-1092.

37. Molnar-Kimber, K.L., Sterman, D.H., Chang, M, ElBash, M, Elshami, A.E., Gelfand,K., Kang, E, Wilson, J.M., Kaiser, L.R., and Albelda, S.M. (1998) Impact of Pre-Existing and Induced Humoral and Cellular Immune Responses in an Adenoviral-based Gene Therapy Phase 1 Clinical Trial for Localized Malignancy (Mesothelioma) Human Gene Therapy 9: 2121-2133.

38. Coukos, G., Caparrelli, D.J., Makrigiannakis, A., Abbas, A.E., Kaiser, L.R., Rubin, S.C., Albelda, S.M., and K. L. Molnar-Kimber. (1999) Use of Producer cells to deliver a replication-selective herpes simplex virus-1 mutant for treatment of Epithelial Ovarian Cancer. Clinical Cancer Research 5:1523-1537.

39. Lambright, E.S., Caparrelli, D.J., Abbas, A.E., Toyoizumi, T., Coukos, G., Molnar-Kimber, K.L., and Kaiser, L.R. (1999). Oncolytic therapy using a mutant type-1 herpes simplex virus and the role of the immune system. Annuals of Thoracic Surgery 68(5):1756-60; discussion 1761-2.

40. Coukos, G., Rubin, S.C., Molnar-Kimber, K.L. (1999) Application of Recombinant Herpes Simplex Virus-1 (HSV-1) for the Treatment of Malignancies Outside the Central Nervous System. Gene Therapy and Molecular Biology 3: 79-89.

41. Toyoizumi, T., Mick, R., Abbas, AE, Kang, EH, Kaiser, LR, Molnar-Kimber, KL. 1999. Combined therapy with Chemotherapeutic Agents and Herpes Simpex Type 1 ICP34.5 mutant (HSV-1716) in Human Non-Small Cell Lung Cancer. Human Gene Therapy 10(18):3013-29

42. Coukos, G., Makrigiannakis, A., Kaiser, L.R., Rubin, S.C., Albelda, S.M., and K. L. Molnar-Kimber. (2000) Treatment of Epithelial Ovarian Cancer with Multi-attenuated Herpes Simplex Virus-1 Mutant, G207. Cancer Gene Therapy 7: 275-283.

43. Coukos, G., Makrigiannakis, A., Kang, E. H., Rubin, S.C., Albelda, S.M., and K. L. Molnar-Kimber. (2000) Oncolytic Herpes Simplex Virus-1 lacking ICP34.5 Induces p53 Independent Cell Death and is Efficacious against Chemotherapy Resistant Ovarian Cancer. Clin. Cancer Res. 6:3342-53.

44. Lambright, E.S., Kang, E.H., Force, S., Lanuti, M., Caparrelli, D.J., Kaiser, L.R., Albelda, S.M., and Molnar-Kimber, K.L. (2000). Effect of Pre-existing anti-herpes immunity on the efficacy of herpes simplex viral therapy in a murine intraperitoneal tumor model. Mol. Therapy 2:387-393.

45. Zhou, T., Guo, J-T, Nunes, F., Molnar-Kimber, K.L., Wilson, J.M., Aldrich, C.E., Saputelli, J., Litwin, S., Condreay, L.D., Seeger, C., and Mason, W.S. (2000). Combination therapy with lamivudine and adenovirus causes transient suppression of chronic woodchuck hepatitis B virus infections. J. Virol. 74:11754-63.

46. Abdul-Ghani, R., Ohana, P., Matouk, I., Ayesh, S., Ayesh, B., Laster, M., Bibi, O., Giladi, H., Molnar-Kimber, K., A. Sughayer, M. A., de Groot, and Hochberg, A. (2000). The use of Transcriptional Regulatory Sequences of Telomerase (hTER and hTERT) for the Selective Killing of Cancer Cells. Mol. Therapy. 2:539-544.

47. Sterman, D.H., Molnar-Kimber, K.L., Iyengar, T., Chang, M., Lanuti, M., Amin, K.M., Pierce, B., Kang, E. H., Treat, J., Recio, A., Litzky, L.A., Wilson, J.M., Kaiser, L.R. and Albelda, S.M. (2000). A controlled trial of systemic corticosteroid administration in conjunction with intrapleural adenoviral administration in patients with malignant mesothelioma. Cancer Gene therapy 7:1511-18.

48. Banet, G., Bibi, O., Matouk, I., Laster, M., Molnar-Kimber, K.L., Tykocinski, M.L., deGroot, N., Hochberg, A., Ohana, P. (2001). Characterization of human and mouse H19 regulatory sequences. Mol. Biol. Reports 27(3):157-65.

49. Blank, S.V., Rubin, S.C., Coukos, G., Amin, K.M., Albelda, S.M. and Molnar-Kimber, K.L. (2002) Replication-selective herpes simplex virus-1 mutant therapy of human cervical cancer is enhanced by low dose radiation. Human Gene Therapy 13:627-639.

50. Tsukuda, K., Wiewrodt, R., Molnar-Kimber, K.L., Jovanovic, V., Amin, K.M. (2002). The characterization of a replication competent adenovirus targeting the critical cell cycle regulator E2F-A Gene Product. Cancer Research, 62:3438-47.

51. Kesmodel S, Prabakaran I, Canter R, Menon C, Molnar-Kimber K, Fraker D. (2005) Virus-mediated oncolysis of thyroid cancer by a replication-selective adenovirus driven by a thyroglobulin promoter-enhancer region. J Clin Endocrinol Metab. 2005 Jun;90(6):3440-8.

Patent application on HSV mutants:

Molnar-Kimber, K.L., Kaiser, L.R., Toyoizumi, T., Combined therapy with chemotherapeutic agents and an oncolytic virus for killing tumor cells in a subject. U.S. patent #6,428,968. Issued August 6, 2002.

In case you’re wondering, where the author is placed on a scientific paper usually tells their role in the scientific studies.

For example, a corresponding author, who is usually listed first or last, has a major responsibility for the research. I'm a corresponding author on many of the above llisted papers. The first author often has done most of the studies whereas the research was often performed in the laboratory of the last author.

As you become an established scientist and writer of numerous publications, various journals request that you review manuscripts submitted to them by other scientists or MDs (peer review).

I’ve been an Adhoc reviewer for: J. of Leukocyte Biology, Infection and Immunity, Human Gene Therapy, Cancer Gene Therapy, Molecular Therapy, J. of Neuroscience, Lancet, Cancer Research, J. National Cancer Institute, International Journal of Cancer.

As noted above, I’ve also been an ad-hoc reviewer for various types of grants for the National Cancer Institute and the Small Business Administration from 1999 – 2006.

A list of my scientific memberships, awards, and teaching experience are listed here.

In summary, my broad research experience includes over 20 years in the pharmaceutical industry, biotechnology industry and in Academia (Universities).

Everyday, I focus my scientific background and training (what questions to ask, view each aspect of disease from many perspectives, view theories with an open mind) to provide you a review of rheumatoid arthritis and new insights.

If you have questions about rheumatoid arthritis, please send them to me because others just like you may also have those questions. Your question may also spur further research that leads to new ideas and ultimately a cure.

Together we can really make a difference.

Please note that the information on this website is a sharing of information and knowledge from the research and experience of Dr. Molnar-Kimber and her community. It is not intended to replace your one on one relationship with a qualified health care professional. It also is not intended to be medical advice. However, it is often observed that patients who take a major interest in their disease and learn as much as they can about their disease and potential treatments often improve faster than those who don’t. Dr. Molnar-Kimber encourages you to make your own health care decisions based upon your own research and discussions with your qualified health care professional.

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