Hemiallogeneic bone marrow transplantation in a child with severe combined immunodeficiency disease

March, 1972 T h e ]ournaI o[ P E D I A T R I C S

Hemiallogeneic bone marro in a chiM

441

transplantation

vitb severe combined

disease i m m u nodehcienc J .J Immunologic reconstitution of a 16-month-old male in[ant with severe combined immunodeficiency disease was attempted using maternal bone marrow cells in the absence of an HL-A-identieal donor. Following transplantation, lymphocytes [rom the recipient became responsive to phytohemagglutinin; Candida albieans, and type 12 M-protein [rom group A beta hemolytic streptococci. Karyotyping [oUowing phytohemagglutinin stimulation revealed that one filth the responsive cells were o[ recipient origin ( X Y ) , Early signs of graft-versus-host reaction were noted by the [ourteenth day. The involvement of skin, lungs, liver, and spleen became worse during the ensuing week, but by the twenty-first day, the patient's condition began to improve. The use o[ methotrexale, bowel sterilization, maternal plasma infusions, and other supportive measures were thought to be responsible [or mitigating the gra[t-versus-host reaction. Despite substantial clearing of the involvement of the lungs, liver, and spleen, the patient died 41 days after transplantation.

Liang-Yeh Frank Wu, M.D., Richard M. Rothberg, M.D., * Lauren M.

Pachman, M.D., L. Warwick Coppleson, M.D., Bernard J. Lamer, M.D., and Raymond D. A. Peterson, M.D., Chicago, Ill.

T i~ r. c o R R F. C T I O N of severe combined immunodeficiency disease with bone marrow transplantation has been shown to be feasible From The LaRabida-Universily o[ Chicago Institute and the Department of Pediatrics, University o[ Chicago. Supported in part by United States Public Health Service Training Grant 5-TO1-AM05539-03, United States Public Health Service Research Grant AI-07854, and General Clinical Research Centers Program Grant RR-305 [rom the National Institutes o[ Health. Reprint address: Richard M . Rothberg, M . D . , Department of Pediatrics, Prltzker School o[ Medicine, 950 E. 59th St., Chicago, Ill. 60637. *Recipient of a United States Public Health Service Research Career Development Award 1-K4-AI-38,899.

when the donor and recipient have been compatible at the major histocompatibility locus ( H L - A ) ? -a However, HL-A-identical donors are unlikely to be found in the general population and only occur in approximately 25 per cent of siblings. ~ With only one exception, 5 unmatched marrow transplants given to patients with severe combined immunodeficiency disease have been promptly followed by death, usually from graftversus-host reaction. 6-1~ This report documents an attempt to correct a severe combined immunodeficiency disease with an unfractionated hemialloVol. 80, No. 3, pp. 441-449

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The Journal o[ Pediatrics March 1972

genetic bone m a r r o w t r a n s p l a n t a n d efforts to m i t i g a t e the expected graft-versus-host reaction. MATERIALS

AND

METHODS

Q u a n t i t a t i v e assays of serum a n d salivary immunoglobulins were done by the r a d i a l diffusion technique of M a n c i n i a n d associates? ~ Skin tests for delayed hypersensitivity included i n t e r m e d i a t e strength purified protein derivatives, histoplasmin, m u m p s antigen, trichophytin, a n d Candida aIbicans. Sensitization with 10 per cent dinitrofluorobenzene ( D N F B ) a n d challenge 14 days later with 1:10,000 a n d 1:5,000 solutions of D N F B was done by the m e t h o d of G o o d a n d associates. 12 I n vitro lymphocyte response to phytohemagglutinin, type 12 M protein, a n d Candida albicans was done as previously described? ~ T h e results are expressed as a stimulation index, calculated by dividing the m e a n counts per m i n u t e of triplicate stimulated cultures by the m e a n counts p e r m i n u t e of triplicate u n s t i m u l a t e d cultures. Blastogenic factor was derived from cultured lymphocytes (5 x 108 lymphoeytes p e r milliliter) o b t a i n e d from k n o w n type 12 M - p o s itive individuals as previously described. .4 K a r y o t y p i c analysis was p e r f o r m e d according to a modification of the m e t h o d of M o o r e h e a d a n d associates? ~ Freshly aspirated bone m a r r o w was processed for transp l a n t a t i o n by the m e t h o d of Bach a n d associates2; 2 • l0 s nucleated cells were given intravenously. CASE

REPORT

Patient D. K., a Caucasian male, was an only child. There was no known family history of immunoglobulin deficiency, lymphoreticular malignancy, or death of relatives in early childhood. Birth weight was 4,032 Gm. A confluent papular rash appeared in the diaper area at 5 days of age and on the neck several days later. A vesiculopapular rash with some hemorrhagic areas was then noted arourfd the ears and on both anterior thighs. At 6 months of age the child began having episodes of wheezing, purulent conjunctivitis, and rhinitis. At 10 months of age he was hospitalized with right lower lobe pneumonia. White biood cell count was 14,300 per cubic millimeter,

and the absolute lymphocyte count 3,100 per cubic millimeter. Serum protein electrophoresis showed total protein, 6.5 Gin. per 100 ml. with gamma globulins, 0.1 Gin. per 100 ml. Thereafter, he received periodic injections of gamma globulin. The pneumonia slowly cleared but recurred at 12 months of age in the right lower lobe. During this hospitalization, mucocutaneous candidiasls and diarrhea were noted. Sermn immunoglobulin levels three days after a 3.0 ml. injection of gamma globulin were IgG, 160 rag. per 100 ml. and IgM and IgA undetectable. The patient was first seen at LaRabida Children's Hospital at the age of 14 months. He weighed 10 Kg. and appeared chronically ill. Tonsils and lymph nodes could not be found, and the liver and spleen were not paIpable. He had right lower lobe pneumonia, purulent rhinitis and conjunctivitis, oral moniliasis, and monilial dermatitis of the groin and back. Coagulase-positive staphylococci were grown from cultures of the nasal discharge and skin. Hemophilus influenzae was isolated from the eonjunctiva. Blood count was normal. The capacity of the patient's neutrophils to phagocytize and kill Staphylococcus aureus 502A was normal. A xylose tolerance test, intestinal fat absorption, 16 and the serum carotene IeveI were compatible with moderately severe malabsorption. Immunologic evaluation. Table I summarizes the immunologic evaluation of the donor and of the patient before and after bone marrow transplantation. The patient's pretransplantation IgG level could be attributed to frequent injections of gamma globulin. Absolute lymphocyte counts were usually normal but occasionally subnormal. The patient's dermal delayed hypersensitivity was absent, and lymphocytes failed to respond to phytohemagglutinin, Candida albicans, streptococcus type 12 M protein, and blastogenic factors. Thus it was obvious that he lacked both humoraI and cellular immune systems. Hospital course. To control infection, the patient was placed in a laminar flow bed a, 1~ and reverse isolation was established. He was given repeated injections of gamma globulin and vigorous antibiotic therapy. Dietary manipulations included a gluten-free diet and a milk substitute containing medium-chain trlglycerides (Portagen). Despite these measures, the diarrhea continued, he failed to gain weight, and slowly deteriorated. It was decided to perform herniallogeneic bone marrow transplantation. All bacteria obtained on serial cultures of feces and pharynx were sensitive to ehloramphenicol and

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Bone marrow transplantation in immunodeficiency disease

44 3

T a b l e I. E v a l u a t i o n of the immunologic competence of the donor a n d p a t i e n t before and after t r a n s p l a n t a t i o n

Immunologic systems Antibody production Immunoglobulins (mg./100 ml.) IgG

IgA IgM Isohemagglutinins Anti-B Salivary IgA Thymus-dependent system Circulating lymphocytes (X 10a/ml.) Skin tests (interdermal) PPD--intermediate Candida Histoplasmin Mumps Tricophytin Sensitization with DNFB

Donor M. K.

Patient D. K. after transplant

90-200 Not detectable Not detectable

920 50 200

i00 ~ l0 20

1:1 Not detectable

1:32 N.D.

N.D. N.D.

800-3,080

5,050

580-6,060

No response No response No response No response No response No response to 1 : 10,000 challenge 1:5,000 vesiculation

N.D. N.D. N.D. N.D. N.D.

Patient D. K. before transplant

In vitro lymphocyte response ~ Phytohemagglutinin

0.2 1

Candida albicans Type 12 M protein

0.4 0.5 1 1

N,D.

N.D. N.D. N.D. N.D.

60

6 7 43 16

4

2

N.D.

4 N.D.

58

1

Blastogenic factort

1 1

N.D. ~- test not done. ~Stlmulatlon index (c.p.m. stimulated culture/c.p.m, unstimulated control subjects). "~Supernatant of lymphocyte cultures responding to 12 M protein; the stimulatory index of normal cells concurrently cultured in the presence of blastogenic factor were greater than 2.0

kanamycin. Prior to transplantation, bowel sterilization was carried out by oral administration of chloramphenicol (100 mg. per kilogram per day) and kanamycin (120 mg. per kilogram per day), and sterile saline enemas were given twice daily for three days. At 16 months of age, immunologic reeonstitution was attempted by giving unfractionated bone marrow cells from his mother. The blood type of both patient and mother was A positive. The patient did well the first few days after transplantation. Pseudomonas aeroginosa appeared in a stool culture obtained on the second day but was not present after discontinuation of the chloramphenicol and kanamycin on Day 5. In order to lessen the severity of the anticipated graft-versus-host reaction, methotrexate 0.25 to 0.5 mg. per kilogram was given intravenously on Days 1, 3, 6, 11, 15,

and 18 and then once weekly? s Repeated maternal plasma transfusions were also given, A summary of the major clinical and laboratory events just prior to and following transplantation is shown on Fig. 1. Transient mild temperature elevations were first noted on Days 12 and 13. Marked temperature elevations and progressive enlargement of the liver and spleen began on Day 14. By Day 16, both organs were 6 cm. below the costal margins. However, repeated liver function tests throughout the course of the illness were normal. A papular eis~thematous rash typical of that seen in graft-versus-host reaction of man 9, 19 appeared on Day 16 on the scalp, face, neck, and upper extremities and rapidly spread to involve the entire body. Severe tachypnea and cyanosis developed, and serial radiographs of the chest showed progressive, diffuse

4 44

Wu etal.

The Journal o/ Pediatrics March 1972

15

2 x I08 Marrow Cells

(ml/kg)

c

N

Motho, ....,e (mg/kg)

~:if

~

Irradiated Packed Cells ~

Plasma

/

Bowel Sterilization

, ~

~ 0 i 0 ,0

l j Saline Enemelllllll

Kanamycml

,

9 ~

-,o

-;

0 0 n

",

0

n

n,

Gentamycin I

IChoramphenicol ~ Nystotie//=====~=ml

Body Weight

,

Ant~hlo.r

= ~

=

~Mothcillin

;

,;

,;

2;

5;

3;

is

,;

S

10

15

20

25

30

3S

40

23

0bs)

I

WBC

t6

(x ]03/m m3 )

12

1 I

~1 Eos I:[] Lymph

-10

-5

~.<~;~

SPLEEN

SKIN

=

LUNG

SALIVARY GLANDS

i ~ f l o

43 15

Stimulation index

~

-,o

-~

- - ' s I

_ ~

"-

,~ ,'5 2'o

-~....

~s

~)

3's

Candida 12 M

4'0

DAYS

Fig. 1. Summary of clinical and laboratory events just prior to and following transplantation. mean counts of .stimulated cultures Stimulation index ~--mean counts of nonstlmulated cultures

bilateral infiltrates (Fig. 2). Arterial bIood gas analysis showed a P% of 39 mm. Hg and Pc% of 27 mm. Hg. He was placed in oxygen and given methicillin and gentamicin, although three blood cultures subsequently proved negative. Approximately one week later the respiratory diffi-

culty subsided, the skin rash began to fade, and the liver and spleen diminished in size. On the twenty-sixth day', bilateral swelling of both parotid and submaxillary glands was noted; it disappeared spontaneously 5 days later. Evidence of cytomegalovirus disease was not demonstrated.

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Bone marrow transplantation in immunodeficiency disease

4 45

Fig. 2. Chest roentgenograms showing the presence of diffuse bilateral infiltrates 16 days after transplantation. On the thirty-second day, the skin eruption became worse. By Day 33, the chest radiograph appeared to be normal. During the last week of life he became lethargic and at times had roiling ocular movements. He died 41 days after transplantation. Repeated blood cuItures up to two days before death reveaIed no growth. Evidence of a change in the patient's immunologic capacities was demonstrated as early as the second day. As shown in Table I and Fig. l, after transplantation the patient's cells became increasingly responsive to type 12 M protein. An increasing responsiveness to phytohemagglutinin was noted 13, 29, and 40 days after transplantation. Prior to transplantation, recipient lymphocytes did not respond to Candida albicans, but 40 days after transplantation, a stimulation index of 16 was obtained with this antigen. The unstimulated control counts were generally elevated over pretransplantation levels. On Day 30, chromosome analysis of peripheral lymphocytes was done; karyotypic analysis of 41 mitotic figures revealed 33 female cells (donor) and 8 male cells (recipient). This analysis was confirmed by 3 independent observers. Cells derived from buecal mucosa and stained with acetoorecin had a negative X-chromatin pattern indicating the presence of only one X chromosome. POSTMORTEM

STUDIES

T h e thymus weighed 1.5 Gm. and was found in the normal location. Microscopi-

cally, each lobule consisted of irregular whorls and nests of epithelial cells with very few lymphocytes (Fig. 3). Hassall's corpuscles were not present, and there was no differentiation into cortex and medulla. N o tonsillar tissue was identified microscopically. L y m p h nodes were generally poorly developed. T h e cortex and medulla were unevenly cellular with scattered loci of aggregated lymphoid cells. T h e aggregates contained a spectrum of pyroninophilic cells ranging in morphology from immunoblasts to plasma cells. T h e spleen was enlarged. Histologically, there was severe congestion of pulp cords. No germinal centers were seen. Small cuffs of lymphoid cells surrounded penicilliary arteries containing many small lymphocytes and, as in the nodes, a few pyroninophilic ceils. Erythrophagocytosis and scattered eosinophils were noted. I n bone m a r r o w there was a marked decrease in erythropoiesis and myelopoiesis with relative eosinophilia. Erythrophagocytosis and pyroninophilic cells with recognizable plasma cells were noted. T h e liver was enlarged. Histologically, hepatic sinusoids were congested. There were lymphoid infiltrations in portal areas similar to those found in lymphoid tissues elsewhere.

446

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The Journal o[ Pediatrics March 1972

Fig. 3. A, Photomicrograph of the thymus showing no differentiation into cortex and medulla, and the absence of Hassall's corpuscles. B, Higher power revealing that the tissue is composed almost entirely of stromal cells. (Hematoxylin and eosin.)

Severe fatty change and central vein sclerosis were noted. Erythrophagocytosis by K u p f f e r cells was found. Ulcerations with bacterial and fungal invasion were noted along the gastrointestinal tract. Very little cellular reaction accompanied these lesions. There were no Peyer's patches, and microscopically no pyroninophilic cells or germinal centers were found.

I n the lungs there was slight septal fibrosis and a diffuse interstitial infiltrate which was most prominent around the small bronchi and terminal bronchioles (Fig. 4). Pyroninophilic cells were scarce. No Pneumocystis carinii were seen. T h e r e was hyperkeratosis with marked parakeratosis, dyskeratosis, and edema of the basal cell layer of skin. T h e r e were peri-

Volume 80 Number 3

Bone marrow transplantation in irnmunodeficiency disease

44 7

Fig. 4. Photomicrograph of the lung showing the prominence of the interstitial infiltrate around the small bronchi and terminal bronchioles. (Hematoxylin and eosin.) vascular infiltrations with lymphocytes and hisfiocytes. Similar perivascular infiltrates were present in skeletal and cardiac muscles. Mild interstitial infiltration was noted in the kidneys. Other tissues, including brain, pancreas, thyroid, and testes, had no diagnostic abnormalities. Pseudomonas aeroginosa was isolated from postmortem cultures of blood, spleen, and lungs. DISCUSSION

Mucocutaneous candidiasis, recurrent infections, diarrhea, failure to thrive, immunoglobulin deficiency, demonstrable defects in cellular immunity, and postmortem findings all indicate that this child had a severe combined immunologic deficiency. The etiology of the deficiency could not be ascertained, but the entire clinical picture was most compatible with a genetic defect, either of a lymphocyte stem cell population or of epithelial structures critical for the differentiation of this stem cell. In either case, the proper development of the circulating lymphocyte populations essential for both cellular immunity and immunoglobulin synthesis was impaired. 2~ In an attempt to correct the immunologic lesion, a bone marrow transplant was per-

formed. Supportive efforts aimed at reducing infection included bowel cleansing with saline enemas, 21 oral antibiotics, 22 and the frequent administration of fresh maternal plasma. I n the absence of an HL-A-identical sibling and a practical way to prevent graftversus-host reaction, the mother rather than the father was chosen as the donor for two reasons. First, she provided a natural karyotypic marker that could be traced in the recipient and second, a mother's immunocompetent cells theoretically may be less reactive to the child's tissue antigens than the father's. 23 T h e methotrexate regimen, demonstrated to establish long-term ,chimerism in irradiated dogs given mismatched bone marrow cells, TM was used in an effort to modify the anticipated graft-versus-host reaction. The data in Table I and the presence of plasma cells in lymphatic tissues at postmortem suggest that the child was at least partially reconstituted by the hemiallogeneic bone marrow transplant. Prior to transplantation, the patient's circulating lymphocytes were not responsive to PHA, type 19 M protein or Candida aIbicans. Following administration, all three mitogens stimulated in vitro D N A synthesis in lymphocytes from the re-

448

W u et al.

cipient. This acquisition of cellular responsiveness can be explained by two mechanisms: either donor ceils were responsible or the transplantation procedure enabled recipient cells to become responsive. If the donor cells were responsibIe, they were either immunocompetent cells or stem cells influenced by the recipient's thymus. This latter possibility is unlikely in view of the near absence of lymphocytic elements in the thymus at postm o r t e m examination. T h e fact that karyotypic analysis in this and one previous patient G revealed recipient cells in mitosis after phytohemagglutinin stimulation suggests that at least some of the response m a y have been due to a newly acquired recipient cell capability. These considerations of the mechanisms whereby bone m a r r o w transplantation affects the i m m u n e system of these patients may provide insight into the pathogenesis of the disease. I n this and previously described cases,6, s, 2, the near absence of lymphocytic elements in the thymus after transplantation suggests that these patients with a combined immunodeficiency state could have a specific thymic lesion which is not corrected by bone m a r r o w transplantation. Clinical graft-versus-host reaction includes the following: diarrhea, anorexia, vomiting, hepatitis, erythematous and exfoliative skin lesions, fever that does not respond to drugs, and infections of bacterial, viral, or yeast origin. 25 In addition to these problems, our patient developed severe dyspnea and pulmonary infiltrates which cleared when the other symptoms of the graft-versus-host reaction diminished. Similar respiratory difficulties have been observed in other patients with graft-versus-host reaction. ~6 T h e postmortem findings were compatible with his primary disease, the graft-versushost reaction, and the effects of methotrexate. T h e contribution of each of these components to the final pathologic picture is difficult to assess but a few speculations are possible. T h e occurrence of immunocytes in lymph nodes, spleen, and bone marrow, and the histiocytic infiltration and erythrophagocytosis noted in the liver, lung, and lymphoid

The Journal of Pediatrics March 1972

organs, are characteristic of graft-versus-host reaction. Both graft-versus-host reaction and methotrexate can cause alimentary mucosal lesions; however, in our patient, the complete absence of a cellular infiltrate, despite the presence of large numbers of bacteria, seems more compatible with methotrexate effect. T h e difficulties encountered in this child emphasize the importance of avoiding graft-versus-host reaction either by selecting a histocompatible donor or by manipulating donor cells to minimize their graft-versushost capability. The authors wish to express their gratitude to Dr. E. Pergament for the cytogenic studies and Dr. Charles Platz for his help in preparing the pathology sections. REFERENCES

1. Meuwissen, H. J., Gatti, R. A., Terasaki, P. I., Hong, R., and Good, R. A.: Treatment of Iymphopenic hypogammagIobulinemla and bone marrow aplasia by transplantation of allogenic marrow, N. Engl. J. Med. 281: 691, 1969. 2. Bach, F. H., Albertini, R. J., Joo, P., Anderson, J. L., and Bortin, M. M.: Bane marrow transplantation in a patient with the WiskottAldrich syndrome, Lancet 2: 1364, 1968. 3. de Koning, J., Dooren, L. J., van Bekkum, D. W., van Rood, J. J., Dicke, K. A., and Radl, J.: Transplantation of bone marrow cells and fetal thymus in an infant with lymphopenic immunological deficiency, Lancet 1" 1223, 1969. 4. Bach, F. H., and Amos, D. B.: Hu-l: Major histocompatibility locus in man, Science 156: 1506, 1967. 5. Buckley, R. H., Amos, D. B., Kremer, W. P., and Stickel, D. L.: Incompatible bone marrow transplantation in lymphopenic immunologic deficiency, N. Engl. J. Med. 285: 1035, 1971. 6. Rosen, F. S., Gotoff, S. P., Craig, J. M., Ritchie, J., and Janeway, C. H.: Further observations on the Swiss type of agammaglobulinemia (alymphocytosis). The effect of syngenlc bone marrow cells, N. Engl. J. Med. 274: 18, 1966. 7. Dooren, L. J., de Vries, M. J., van Bekkum, D. W., Cleton, F. J., and de Koning, J.: Sex-linked thymic epithelial hypoplasla in two siblings, J. PEDIATR. 72: 51, 1968. 8. Hong, R., Kay, H. E. M., Cooper, M. D., Meuwissen, H., Allan, M. J. G., and Good, R. A.: Immunological restriction in lymphopenic immunological deficiency syndrome, Lancet l: 503, 1968.

Volume 80 Number 3

Bone marrow transplantation in immunodeficiency disease

9. Miller, M. E.: Thymic dysplasia ("Swiss agammaglobulinemia"), J, P~I~IA:rR. 70: 730, 1967. i0. Kretschmer, R., Jeannet, M., Mereu, T. R., Kretschmer, K., Winn, H., and Rosen, F. S.: Hereditary thymic dysplasia: A graftversus-host reaction induced by bone marrow cells with a partial 4a series histocompatibility, Pediatr. Res. 3: 34, 1969. 11. Mancinl, G., Carbonara, A. O., and Hereroans, J. Iv.: Immunochemical quantitatlon of antigens by single radial immunodiffusion, Immunochemistry 2: 235, 1965. 12. Good, R. A., Kelly, W. D., Rostein, J., and Varco, R. L.: Immunological deficiency diseases, Progr. Allergy 6: 283, 1962. 13. Dau, P. C., and Peterson, R. D. A.: Transformation of lymphocytes from patients with multiple sclerosis, Arch. Neurol. 23: 32, t970. 14. Pachman, L. M., Lau, S., and Fox, E. N.: In vitro correlates of delayed hypersensitivity and phagocytosis using streptococcal M protein, Fed. Proc. 30: 648, 1971. 15. Moorhead, P. S., Nowell, P. C., Mellman, W. J., Battips, D. M., and Hungerford, D. A.: Chromosome preparations of leukocytes cultured from human peripheral blood, Exp. Cell Res. 20: 613, 1960. 16. Goldbloom, R. B., and Blake, R. M.: Assessment of three methods for measuring intestinal fat absorption in infants and children, Pediatrics 34: 814, 1964. 17. Husgar, R. J.: Air curtains for patient isolation, J. A. M. A. 907: 549, 1969. 18. Storb, R., Epstein, R. B., Graham, T. C , and Thomas, E. D.: Methotrexate regimens for control of graft-versus-host disease in dogs with alIogenic marrow grafts, Transplantation 9: 240, 1970.

449

19. Math6, G., Amiel, J. L., Schwarzenberg, L., Cattan, A., Schneider, M., de Vries, M. J., Tubiana, M., Latranne, C., Binet, J. L., Papiernik, M., Seman, G., Matsukura, M., Mew, A. M., Schwarzmann, V., and Flaisler, A.: Successful allogenic bone marrow transplantation in man: Chimerism, induced specific tolerance and possible anti-leukemic effects, Blood 25: 179, 1965. 20. Peterson, R. D. A., Cooper, M. D., and Good, R. A.: The pathogenesis of immunologic deficiency diseases, Am. J. Med. 38: 579, 1965. 21. Martin, L. W., Altemeier, W. A., and Reyes, P. M., Jr.: Infections in pediatric surgery, Pediatr. Clin. North Am. 16: 735, 1969. 22. Keast, D.: A simple index for the measurement of the runting syndrome and its use in the study of the influence of the gut flora in its production, Immunology 15: 237, 1968. 23. Uphoff, D. E.: Maternal modification of tissue antlgenlcity and prevention of the graftversus-host reaction, Exp. Hematol. 20: 11, 1970. 24. Lawton, A. R., Bockman, D. E., and Cooper, M. D.: Treatment of autosomal recessive lymphopenlc agammaglobulinemla by transplantation of matched allogenic bone marrow. In press. 25. Congdon, C. C.: Cooperative group on bone marrow transplantation in man, Exp. Hematol. 20: 97, 1970. 26. Chomette, G., Math6, G., Auriol, M., Brocheriou, C., and Pinaudeau, Y.: Le syndrome secondaire chez l'homme, Virchows Arch. (Pathol. Anat.) 349: 98, 1970.