Experience with human fetal adrenal transplant in relieving pain in advanced rheumatoid arthritis.
The present study was aimed at examining the role of developing fetal adrenal transplant in cases of old rheumatoid arthritis with severe pain due to involvement of the inflammatory and neuropathic components of pain. Human fetal adrenal transplant survives in HLA randomized adult hosts with rheumatoid arthritis and has a beneficial effect on pain and inflammation.
During intra-uterine growth, the human fetus passes through the pre-immune (before 15 weeks) and subsequently, the hypo-immune phases of growth and maturation. In these phases, there is a lack of proper antigenic expression of the growing human fetus in utero, which provides an excellent opportunity for fetal cell/ tissue/ organ transplantation in its pre-HLA state of growth and maturation. This is on the assumption that hypo-antigenic naive fetal cells would not be targeted by the hosts' HLA system. In this context, another interesting phenomenon must be pointed out, and that is, the 'homing' behaviour of the transplanted cell, which, if seen from the positive angle, implies that the fetal premature cells (stem cells) with high telomerase ribo nucleoprotein complex, have the potentiality to replace damaged cells or cells in their senescence, and thus augment the overall state of health of the tissue or organ in question. (1)
We are a group of investigators working since 1979 on the process through which the human fetus acquires immunocompetence. (2-7) Earlier, we have reported on the safety of fetal cell transplant, viz., umbilical cord whole blood transplant in adults. (8,9) We have also communicated our findings after the successful transplantation of a human fetal organ, i.e., thymus, in the HLA randomized adult axilla, to combat leucopenia in the background of non-Hodgkin's lymphoma.10 Transplantation of human dopamine neurons in the brain, (to be more precise, the CT guided stereotactic placement of embryonic mesencephalic tissue in the putamen or putamen and caudate region), has resulted in a marked clinical improvement in patients suffering from Parkinsonism. (11) Adrenal cortical cells' xeno-transplantation has been attempted earlier in SCID mice (severe combined immuno-deficiency), which eventually got vascularized and secreted steroid that replaced those from the animals' own adrenal glands, which were removed during the transplantation surgery. (12) Cell transplantation techniques have now provided researchers with a way to comprehend the regulation of cell proliferation in the same cell type, in cell culture or in a vascularized tissue structure in a host animal. The contrasting role of p57(KIP2) and p21(Waf1/CIP1/SDI1) in transplanted human and bovine adreno-cortical cells have also been reported. (13) In Addison's disease, there is a report of a successful allo-transplantation of embryonal adrenal tissue. (14) There are also interesting reports of adrenal medullary transplant or purified adrenal chromaffin cells' transplant for the managemant of chronic pain, (15) and pain of central origin after spinal cord hemisection, (16) and in cases of intractable cancer pain. (17,18) Hence, the successful development of fetal cell/ tissue transplantation in adults has improved the possibility of eventual therapeutic solutions in a variety of intractable diseases.
In the current paper, we have examined the effect of human fetal adrenal (within 20 weeks, i.e., the legal limit of hysterotomy and ligation) transplant in patients with advanced rheumatoid arthritis with intractable pain not relieved with non-steroidal inflammatory drugs, disease modifying anti-rheumatic drugs like D-penicillamine, methotrexate, gold compounds, anti-malarials and sulfasalazines, and/ or glucocorticoids, with a view to assessing the impact of the human fetal adrenal gland transplantation in relieving pain of inflammatory and neuropathic origin in cases of long standing rheumatoid arthritis.
KEY WORDS : Human Fetal Adrenal Transplant; Rheumatoid Arthritis; Pain Relief
Materials And Methods :
Ten patients were admitted with advanced rheumatoid arthritis (suffering from five years to 15 years), who presented with four of the seven 1987 revised criteria of the American College of Rheumatology for diagnosis of rheumatoid arthritis. (19) The revised criteria are: morning stiffness, arthritis of three or more joint areas, arthritis of hand joints, symmetric arthritis, like bone erosion, decalcification adjacent to the involved joints, etc. The ultimate goals of therapy in rheumatoid arthritis are relief of pain, reduction of inflammation, protection of the articular structures and their functions, and finally, control of systemic involvement.
These patients were included in the fetal adrenal gland transplant programme after taking informed consent from the patients' guardians and seeking due approval from the institutional ethical committee, who discussed the pros and cons about the use of electively aborted fetal tissue, and advised us to continue the research within the framework of legal and ethical safeguards. The committee also discussed the possibility of developing clinical benefits of this research for this intractable disease, giving due consideration to privacy, safety and also eliminating the possibility of secondary gain as a reason to decide in favour of an abortion.
Following standard antiseptic, aseptic and pre-medication protocol, a suitable axillary site was prepared in each of the victims of rheumatoid arthritis, using one percent lignocaine infiltration anaesthesia. A 2.5 centimeter long and 2 centimeter deep tissue space was dissected and prepared in each patient, using diathermy and knife. A fetus was collected from a consenting mother undergoing hysterotomy and ligation (up to 20 weeks) under general anaesthesia, for each case. Within a minute of hysterotomy, the fetus and the intact sac were taken out and brought to the transplant recipient's table. The second group of surgeons who had prepared the graft sites in the axilla of the arthritis patients, immediately dissected the fetus from the intact amniotic cavity and took out the adrenal gland from the fetus within a few seconds, and transplanted the fetal adrenal into the prepared site in the axilla of the arthritis patient. The skin was then closed with (00) vicryl atraumatic interrupted sutures. Haematological parameters (Hb, Tc, Dc, ESR, platelet) were studied in the pre-operative phase and continued post-operatively up to six weeks from the date of transplantation. After one to three months from the date of fetal tissue placement, some tissue was retrieved with a small elliptical incision under local anaesthesia (1 percent lignocaine) for serial histological evaluation by Haematoxylin and Eosin stain, PAS stain, Van Gieson, Reticulin stain., and Giemsa stain as per standard protocol. The tissue retrieval site was closed by (00) atraumatic vicryl. The impact of fetal adrenal transplantation on pain relief was assessed by the specifications of the short form of the McGill questionnaire. (20) We have also incorporated the impact of age differences in the quality of chronic pain. (21)
Result And Analysis :
Our understanding about the pathophysiology of rheumatoid arthritis (RA) is rapidly changing. There is realization that damage occurs early and early treatment is a critical determinant in long-term therapy. (22) The last decade has also witnessed the rebirth of steroid (23) and nearly universal acceptance of combination therapy, (24) and lastly, a recent emphasis on biological therapy, specially, TNF-alpha inhibition (25) has been a breakthrough in the clinical approach to remission. Glucocorticoids provide a definite relief in rheumatoid arthritis for pain and mobility in the early stages of the disease. Between 15 to 40 percent of the patients suffering from rheumatoid arthritis take glucocorticoids at any given time in many North American and European clinics. (26) Hench PS et al (27) first wrote about the therapeutic use of glucocorticoids to combat rheumatoid arthritis. Both acute phase response and the severity of the disease activity were controlled by glucocorticoids for the initial three to six months. It is possible that the benefit of glucocorticoids is masked by an increasing response to other anti-rheumatoid therapy. The American College of Rheumatology (ACR) (28) revised criteria for treatment is well-meaning and helpful in treatment guidance, but strictly speaking, the criteria are not optimal in distinguishing early rheumatoid arthritis from undifferentiated polyarthritis and systemic lupus erythematosus. As per the suggestions of the ACR, one to three years of the disease process is considered as early disease.
The problem is somewhat different in developing countries, due to the poor socio-economic and educational backgrounds of the majority of the patients. Here, for the most part, non-compliance with the suggested drug starts as soon as there is some relief. We frequently come across poor patients with intractable pain due to progression of the rheumatoid arthritis, with the involvement of inflammatory and neuropathic components of the disease.
The ultimate goal in the therapy of rheumatoid arthritis is primarily reduction and relief of the pain and inflammation, and secondarily maintenance of the functions and protection of the articular structures and systemic involvement. The following ten cases, all of whom were suffering from intractable pain and inflammation not responding to standard anti-rheumatic therapy as mentioned above, were included for the present study. Details regarding the human fetal adrenal gland transplant are given in the following table.
In Tables 1 and 2, we have shown the clinical effects of human fetal adrenal transplant (up to 20 weeks, viz., the legal limit for medical termination of pregnancy) in patients with long standing rheumatoid arthritis, who did not respond to medical treatments done earlier. What transpires from the study is the universal pain relief of varying degrees (total relief in 60 percent of the patients and partial relief in 40 percent) on the thirtieth day of transplantation, along with reduction of swelling in varying degrees (total reduction in 60 percent of the patients and partial in 40 percent). However, in the case of restoration of mobility, 20 percent of the patients did not show any improvement, due to associated bony and fibrous ankylosis involving multiple joints. We have referred these cases for surgical treatment.
Another interesting observation was the sense of well being in 80 percent of the patients, with a gain in weight (three pounds or more) in 80 percent of the patients enrolled for this study. We are presently assessing the diurnal variations of cortisol and variations of epinephrine along with its urinary metabolites, and also the excretion of the Na and K in the 24 hour urine of the recipients of the fetal adrenal transplants. We also continued thorough clinical monitoring of all vital parameters. Whether fetal tissue with its many unique properties has a growth promoting role is also being investigated by us through a serial estimation of [p.sup.21] and [p.sup.27] levels on the recipients of the transplanted fetal tissue.
Though the fetal tissue was transplanted in sex and HLA randomized adult axillas without concomitant immuno-suppressives or radiation support to blunt the hosts' immune response, serial estimation of the peripheral blood of the hosts did not show any gross leucocytosis or lymphocytosis within the first six weeks of the observation period. The site of transplantation was also found to be healthy in all cases. Further, the retrieved tissue histology showed the proliferation and growth of the fetal tissue in the adult axilla, while at the same time, any feature of inflammation or immunological rejection, viz., mononuclear invasion, thrombosis, endarteritis, justifying graft vs. host reaction, was conspicuously absent. (Vide microphotograph 1-12).
Discussion And Conclusion :
Rheumatoid arthritis is a serious chronic disorder affecting one percent of the population at large. (29) Clinical researchers have tried to achieve pain relief and remission of the disease with various permutation and combinations of steroid, non-steroidal anti-inflammatory drugs, anti-malarials and different disease modifying drugs. However, according to a clinical investigator, the efficacy of the drug becomes progressively modest in advanced rheumatoid arthritis. (30) From Minocycline to combat (?) infective aetiology of arthritis, (31) to gene therapy have been attempted by scientists working in the field. (32) In a phase I study, researchers tried to introduce interleukin-I receptor antagonist in a cDNA encoding mechanism into the knuckle joints of a patient with advanced rheumatoid arthritis, with the idea that genes could serve as a biological delivery vehicle for the products they encode and thus it would be a targeted delivery system for the proteins and RNA and improve their efficacy while providing a longer duration of effects and potential safety.
Another pertinent theoretical question is the structural and functional damage of the patients' own adrenal gland with long standing rheumatoid arthritis directly by the disease process or indirectly by the steroid induced suppression of the adrenal gland in case of patients who took glucocorticoids for remission. Cellular/ tissue adrenal medullary and cortical transplantation may have a role in replenishing the damaged adrenal medullary and cortical cells through the positive intrinsic homing effect of the transplanted cell. It is known that DNA damage of an organ is common in sepsis, shock and other critical medical conditions. In case of DNA damage, there should be either activation of apoptosis, or potential repair of the damage by the activation of cyclin dependent kinase inhibitor p21. (33) Investigators have shown that chemical perfusion injury/ infection/ sepsis, can cause damage to the adrenal cortex as shown by labeling 31 termini of single strand breaks with terminal transferase, in the rat model. (34) Analyzing our own findings, it is interesting to note that our ultimate objective of pain relief was consistently achieved on the thirtieth day of transplantation with 60 percent of the patients reporting complete reief of the pain and 40 percent reporting partial relief. There was also improvement in the mobility of the patients in 80 percent of the cases (20 percent complete remission) and reduction of swelling in 100 percent of the patients, with 60 percent complete reduction. This relief of pain and reduction in the swelling and improvement in mobility, (due to reduction of pain) actually started within 15 days. In all the cases, the transplant scar was healthy, and there was no irritation or hypertrophy of the scar. Although in patient No.4 (R.L.), the transplanted tissue was partially retrieved more than three months later, and in patients Nos. 5 (S.R.) and 6 (S.K.), tissue retrieval was done after two and a half months, the clinical remission continued in all the patients.
The most important and fundamental question to which there is yet no answer, however, is that there was no inflammatory or immunological reaction, as assessed by the hosts' blood sequential study report of total count (Tc) and differential count (Dc). The histology of the retrieved tissue also did not show any inflammatory or immunological reaction.(Vide micrograph 1-12).. We have had similar experiences with other fetal tissue transplants, like umbilical cord whole blood transfusion, (35,36) thymus transplant, (37) lung, heart, pancreas transplants, (38) which were transplanted in the vascular subcutaneous axillary fold. Hence, we are of the opinion that non-rejection of the transplanted fetal tissue (upto 20 weeks) is universal. It is a known fact that certain tiisues in the human body enjoy a certain degree of immunological privileges, for instance, the cornea, the decidua of the uterus, cartilage, and the brain to some extent. But, the human axilla has never been cited as an immunologically privileged site. It is generally believed by biological scientists that the human fetal growth is dependent on an unique symbiotic environment where the mother provides all the necessary support for human fetal growth, proliferation and differentiation. The fetal micro-environment is distinctly different from the adult neuro-endocrine and metabolic micro-environment. (39) Therefore, it is possible that the transplanted fetal adrenal tissue adjusts its own micro-environment to an altered metabolic and immunological situation, using its naive pre-immune or hypo-immune status to prevent immune recognition of the host. Why and how the fetal adrenal tissue in a sex and HLA randomized non-primed (no immunosuppressive support or radiation) host escapes the immunological or inflammatory recognition system, and becomes a human homologous chimera, is a mystery to be solved in the future. However, on the basis of our direct experiences as mentioned earlier, we strongly believe that the hypo-antigenicity of the fetal tissue is the most important factor in preventing the hosts' recognition of the fetal tissue, which thus escapes rejection.
Furthermore, the question may be raised as to why there is pain relief in cases of advanced arthritis with inflammation and neuropathy after transplanting fetal adrenal tissue. The answer to this question is the fact that the survival of the fetal adrenal tissue in the host, with its medullary component, contributes to the release of endorphin and other related compounds which help in lessening the pain. (40.41,42) The transplanted young cortical cells may actively participate in steroid synthesis and release, (43,44,45) and thus eventually play an anti-inflammatory role, the details of which are now being studied by us.
The suprarenal gland develops from a mesodermal portion which forms the cortex and an ectodermal portion which forms the medulla by the participation of cells from the sympathetic system (neuronal crest cell), which invades the medial aspect of the fetal cortex. These cell stain yellow brown with the chrome salts and hence are called chromaffin cells. (46) The fetal adrenal cortex is differentiated by 8 to 9weeks gestational age into a thick inner fetal zone and a thin outer definitive zone, the source of cortisol and the forerunner of the adult cortex. For steroidogenic effect, participation of fetal ACTH is essential from 15-20 weeks of gestational age. In the present publication we are showing the histological photomicrographs of two patients (S.R and S.K). Both the patients carried their 20 weeks fetal adrenal transplants for 2 months and 19 days in their respective axillas before the retrieval of the transplants. During dissection of the transplanted tissue after its elliptical excision from the host's axilla , patchy whitish areas were seen at the transplanted tissue site which did not have any specific configuration of the fetal adrenal gland. This tissue was selected for histology.
Histological microphotograph of the residual tissues of a 20 weeks human fetal adrenal transplant retrieved 2 months 19 days after its placement in the axilla of the patient (S.K) suffering from advanced rheumatoid arthritis. Microphotograph-1 is a low power (80 times) H.E stain picture. Microphotograph-2 is a high power (275 times) PAS stain picture. Microphotograph-3 is a low power (80 times) picture of PAS stain. Microphotograph-4 is a low power (80) V.G stain picture. Microphotograph-5 is a low power reticulin stain picture. Microphotograph-6 is a scan power (25 times) reticulin picture.
Histological microphotograph of the residual tissues of a 20 weeks human fetal adrenal transplant retrieved 2 months 19 days after its placement in the axilla of the patient (S.R) suffering from advanced rheumatoid arthritis. Microphotograph-7 shows the V.G stain picture under scan power (25 times magnification). Microphotograph-8 shows the V.G stain in low power (80 times). Microphotograph-9 shows the H.E stain in scan power (25 times). Microphotograph-10 shows the reticulin stain low power (80 times) picture. Microphotograph-11 shows the high power (275 times) PAS stain picture. Microphotograph-12 shows the scan power (25 times) PAS stain picture.
Histological Conclusions : As per classical HLA concept, unmatched tissues/cells are rejected (excepting in case of syngenic tissue), unless the recipient of the grafted tissue is primed with proper dosage of radiation or immunosuppressives to delay the rejection. This rejection is a vascular phenomenon with histological evidences of thrombosis, mononuclear invasion, endarterites, etc. If we examine all the microphotographs (1-12) critically, we find that histological evidences of rejection of the grafted tissue are conspicuously absent in all the photographs. What is intriguing is the absence of even an inflammatory response against the 20 weeks old grafted fetal adrenal tissue by the hosts' immune response. However, there are evidences of host and graft cell-to-cell interaction with disintegration of the fetal stromal supporting tissue of the transplanted fetal adrenal gland. There are histological evidences which suggest that the adrenal medullary and cortical cells are growing in a scattered and independent manner at the axillary subcutaneous tissue site. Under normal circumstances, transplant rejection, i.e., hyper-acute, acute and even chronic rejection, takes place within a stipulated period of one month, but in this case of fetal adrenal transplant (20 weeks fetal gestational age), no such transplant rejection appears to have occurred as per histological evidences even after 2 months and 19 days.
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Niranjan Bhattacharya *, Shyama Prasad Das *, Mahua Bhattacharya *, Sanjukta Bhattacharya (#)
* Bijoygarh State Hospital, Calcutta, India.
(#) Jadavpur University, Calcutta.
Table 1 List of HLA randomized patients who underwent fetal adrenal transplant. Name Age Sex Date of Date of Condition Transplant Transplant of transplant fetal age Tissue site retrieval P.P. 65 M 19.9.2001 19.10.2001 Healthy 16 weeks T.K.D. 64 M 19.9.2001 19.10.2001 -do- 16 weeks D.K. 59 F 27.7.2001 6.9.2001 -do- 18 weeks R.I. 71 F 27.7.2001 3.11.2001 -do- 18 weeks S.R. 63 M 18.6.2001 6.9.2001 -do- 20 weeks S.K. 59 F 18.6.2001 6.9.2001 -do- 20 weeks I.M. 50 F 27.3.2001 18.5.2001 -do- 16 weeks K.B. 67 F 27.3.2001 18.5.2001 -do- 16 weeks M.D. 76 F 19.8.2001 19.10.2001 -do- 18 weeks B.G. 58 F 19.6.2001 18.9.2001 -do- 16 weeks Name Systemic History response of drug intake P.P. No a.b.c.d. leucocytosis/ * lymphocytosis T.K.D. -do- -do- D.K. -do- -do- R.I. -do- -do- S.R. -do- -do- S.K. -do- -do- I.M. -do- -do- K.B. -do- -do- M.D. -do- -do- B.G. -do- -do- a : Non-steroidal anti-inflammatory drugs b : Disease modifying anti-rheumatic drugs c : Antibiotics like minocycline d : Glucocorticoid Table 2 Assessing the Clinical Impact of Fetal Adrenal Transplant in Cases of Rheumatoid Arthritis Name Pain 15 Swelling Mobility Pain 30 Swelling days 15 days 15 days days 30 days P.P. PR PR PR CR CR TKD -do- -do- -do- -do- -do- D.K. NR NR NR PR PR R.I. PR PR PR CR CR S.R. -do- -do- -do- -do- -do- S.K. -do- -do- -do- -do- -do- I.M. -do- -do- -do- -do- -do- K.B. NR NR NR PR PR M.D. PR PR PR PR -do- B.G. NR NR NR PR -do- Mobility Weight Sense of it 30 days Gain 30 Well being days 30 days P.P. CR 31bs present TKD -do- 41bs -do- D.K. PR 31bs absent R.I. -do- 51bs present S.R. -do- 21bs -do- S.K. -do- -do- -do- I.M. -do- 21bs -do- K.B. NR 31bs -do- M.D. PR -do- -do- B.G. NR -do- absent PR--partial response/ relief/reduction NR--no response/ relief/ reduction CR--complete response/ relief/ reduction * In all the cases mentioned above, pain was gauged on the basis of assessment according to the short form of the McGill questionnaire. In assessing mobility and swelling, both subjective (patient) and objective (medical consultant) criteria have been incorporated. We started to reduce the dosage of the pain relieving drugs as soon as the patient started to feel better.
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|Author:||Bhattacharya, Niranjan; Das, Shyama Prasad; Bhattacharya, Mahua; Bhattacharya, Sanjukta|
|Publication:||Trends in Biomaterials and Artificial Organs|
|Date:||Jan 1, 2004|
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